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{{PBB|geneid=4303}}
{{PBB|geneid=4303}}
'''Forkhead box protein O4''' is a [[protein]] that in humans is encoded by the ''FOXO4'' [[gene]].<ref name="pmid7529552">{{vcite2 journal | vauthors = Parry P, Wei Y, Evans G | title = Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family | journal = Genes Chromosomes Cancer | volume = 11 | issue = 2 | pages = 79–84 | date = Feb 1995 | pmid = 7529552 | pmc = | doi = 10.1002/gcc.2870110203 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: MLLT7 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 7| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4303| accessdate = }}</ref> It is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533.<ref>http://ghr.nlm.nih.gov/gene/FOXO4#location</ref>
'''Forkhead box protein O4''' is a [[protein]] that in humans is encoded by the ''FOXO4'' [[gene]].<ref name="pmid7529552">{{cite journal | vauthors = Parry P, Wei Y, Evans G | title = Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family | journal = Genes Chromosomes Cancer | volume = 11 | issue = 2 | pages = 79–84 | date = Feb 1995 | pmid = 7529552 | pmc = | doi = 10.1002/gcc.2870110203 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: MLLT7 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 7| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4303| accessdate = }}</ref> It is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533.<ref>http://ghr.nlm.nih.gov/gene/FOXO4#location</ref>


== Structure and function ==
== Structure and function ==


FOXO4 is a member of the forkhead family transciption factors O subclass, which is characterized by a winged helix domain used for DNA binding.<ref>{{vcite2 journal | vauthors = Weigel D, Jäckle H | title = The fork head domain: a novel DNA binding motif of eukaryotic transcription factors? | journal = Cell | volume = 63 | issue = 3 | pages = 455–456 | date = Nov 1990 | pmid = 2225060 }}</ref><ref>{{vcite2 journal | vauthors = Kaestner KH, Knochel W, Martinez DE | title = Unified nomenclature for the winged helix/forkhead transcription factors | journal = Genes & Development | volume = 14 | issue = 2 | pages = 142–146 | date = Jan 2000 | pmid = 10702024 }}</ref> There are 4 members of the FOXO family, including [[FOXO1]], [[FOXO3]], and [[FOXO6]]. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation.<ref>{{vcite2 journal | vauthors = van der Horst A, Burgering BM | title = Stressing the role of FoxO proteins in lifespan and disease | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 6 | pages = 440–450 | date = Jun 2007 | pmid = 17522590 | doi = 10.1038/nrm2190 }}</ref> Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis.<ref>{{vcite2 journal | vauthors = van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP | title = FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling | journal = The Biochemical Journal | volume = 391 | issue = Pt 3 | pages = 623–629 | date = Nov 2005 | pmid = 15987244 | doi = 10.1042/BJ20050525 }}</ref><ref>{{vcite2 journal | vauthors = Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A | title = Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 32 | pages = 11278–11283 | date = Aug 2005 | pmid = 16076959 | doi = 10.1073/pnas.0502738102 }}</ref><ref>{{vcite2 journal | vauthors = Boura E, Silhan J, Herman P, Vecer J, Sulc M, Teisinger J, Obsilova V, Obsil T | title = Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding | journal = The Journal of Biological Chemistry | volume = 282 | issue = 11 | pages = 8265–8275 | date = Mar 2007 | pmid = 17244620 | doi = 10.1074/jbc.M605682200 }}</ref><ref>{{vcite2 journal | vauthors = Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD | title = Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification | journal = Nucleic Acids Research | volume = 35 | issue = 20 | pages = 6984–6994 | pmid = 17940099 | doi = 10.1093/nar/gkm703 }}</ref><ref>{{cite journal | pmid = 18786403 | pages = 1407–1416 }}</ref> Two of the main upstream regulators of FOXO4 activity is [[PI3K|phosphoinositide 3- kinase]] (PI3K) and serine/threonine kinase [[AKT|AKT/PKB]].<ref>{{vcite2 journal | vauthors = Manning BD, Cantley LC | title = AKT/PKB signaling: navigating downstream | journal = Cell | volume = 129 | issue = 7 | pages = 261–1274 | date = Jun 2007 | pmid = 17604717 | doi = 10.1016/j.cell.2007.06.009 }}</ref><ref>{{vcite2 journal | vauthors = Calnan DR, Brunet A | title = The FoxO code | journal = Oncogene | volume = 27 | issue = 16 | pages = 2276–2288 | date = Apr 2008 | pmid = 18391970 | doi = 10.1038/onc.2008.21 }}</ref> Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.
FOXO4 is a member of the forkhead family transciption factors O subclass, which is characterized by a winged helix domain used for DNA binding.<ref>{{cite journal | vauthors = Weigel D, Jäckle H | title = The fork head domain: a novel DNA binding motif of eukaryotic transcription factors? | journal = Cell | volume = 63 | issue = 3 | pages = 455–456 | date = Nov 1990 | pmid = 2225060 }}</ref><ref>{{cite journal | vauthors = Kaestner KH, Knochel W, Martinez DE | title = Unified nomenclature for the winged helix/forkhead transcription factors | journal = Genes & Development | volume = 14 | issue = 2 | pages = 142–146 | date = Jan 2000 | pmid = 10702024 }}</ref> There are 4 members of the FOXO family, including [[FOXO1]], [[FOXO3]], and [[FOXO6]]. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation.<ref>{{cite journal | vauthors = van der Horst A, Burgering BM | title = Stressing the role of FoxO proteins in lifespan and disease | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 6 | pages = 440–450 | date = Jun 2007 | pmid = 17522590 | doi = 10.1038/nrm2190 }}</ref> Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis.<ref>{{cite journal | vauthors = van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP | title = FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling | journal = The Biochemical Journal | volume = 391 | issue = Pt 3 | pages = 623–629 | date = Nov 2005 | pmid = 15987244 | doi = 10.1042/BJ20050525 }}</ref><ref>{{cite journal | vauthors = Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A | title = Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 32 | pages = 11278–11283 | date = Aug 2005 | pmid = 16076959 | doi = 10.1073/pnas.0502738102 }}</ref><ref>{{cite journal | vauthors = Boura E, Silhan J, Herman P, Vecer J, Sulc M, Teisinger J, Obsilova V, Obsil T | title = Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding | journal = The Journal of Biological Chemistry | volume = 282 | issue = 11 | pages = 8265–8275 | date = Mar 2007 | pmid = 17244620 | doi = 10.1074/jbc.M605682200 }}</ref><ref>{{cite journal | vauthors = Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD | title = Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification | journal = Nucleic Acids Research | volume = 35 | issue = 20 | pages = 6984–6994 | pmid = 17940099 | doi = 10.1093/nar/gkm703 }}</ref><ref>{{cite journal | pmid = 18786403 | pages = 1407–1416 }}</ref> Two of the main upstream regulators of FOXO4 activity is [[PI3K|phosphoinositide 3- kinase]] (PI3K) and serine/threonine kinase [[AKT|AKT/PKB]].<ref>{{cite journal | vauthors = Manning BD, Cantley LC | title = AKT/PKB signaling: navigating downstream | journal = Cell | volume = 129 | issue = 7 | pages = 261–1274 | date = Jun 2007 | pmid = 17604717 | doi = 10.1016/j.cell.2007.06.009 }}</ref><ref>{{cite journal | vauthors = Calnan DR, Brunet A | title = The FoxO code | journal = Oncogene | volume = 27 | issue = 16 | pages = 2276–2288 | date = Apr 2008 | pmid = 18391970 | doi = 10.1038/onc.2008.21 }}</ref> Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.


== Clinical significance ==
== Clinical significance ==
Line 10: Line 10:
=== Associations with longevity ===
=== Associations with longevity ===


FOXO transcription factors have been shown to be the down downstream effector molecules of [[Insulin-like growth factor|insulin-like growth factor (IGF) signaling pathway]]. In the absence of insulin, PI3K is inactive so FOXO is able to translocate to the nucleus and turn on many genetic pathways associated with longevity.<ref>{{vcite2 journal | vauthors = Neumann-Haefelin E, Qi W, Finkbeiner E, Walz G, Baumeister R, Hertweck M | title = SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans | journal = Genes & Development | volume = 22 | issue = 19 | pages = 2721–2735 | date = Oct 2008 | pmid = 18832074 | doi = 10.1101/gad.478408 }}</ref> FOXO’s ability to restrict this pathway produces an increase in lifespan for worms, flies, mice, and correlates to longer human lives as well.<ref>{{vcite2 journal | vauthors = Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R | title = A C. elegans mutant that lives twice as long as wild type | journal = Nature | volume = 366 | issue = 6454 | pages = 461–464 | date = Dec 1993 | pmid = 8247153 | doi = 10.1038/366461a0 }}</ref><ref>{{vcite2 journal | vauthors = Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD | title = FOXO3A genotype is strongly associated with human longevity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 37 | pages = 13987–13992 | date = Sep 2008 | pmid = 18765803 | doi = 10.1073/pnas.0801030105 }}</ref>
FOXO transcription factors have been shown to be the down downstream effector molecules of [[Insulin-like growth factor|insulin-like growth factor (IGF) signaling pathway]]. In the absence of insulin, PI3K is inactive so FOXO is able to translocate to the nucleus and turn on many genetic pathways associated with longevity.<ref>{{cite journal | vauthors = Neumann-Haefelin E, Qi W, Finkbeiner E, Walz G, Baumeister R, Hertweck M | title = SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans | journal = Genes & Development | volume = 22 | issue = 19 | pages = 2721–2735 | date = Oct 2008 | pmid = 18832074 | doi = 10.1101/gad.478408 }}</ref> FOXO’s ability to restrict this pathway produces an increase in lifespan for worms, flies, mice, and correlates to longer human lives as well.<ref>{{cite journal | vauthors = Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R | title = A C. elegans mutant that lives twice as long as wild type | journal = Nature | volume = 366 | issue = 6454 | pages = 461–464 | date = Dec 1993 | pmid = 8247153 | doi = 10.1038/366461a0 }}</ref><ref>{{cite journal | vauthors = Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD | title = FOXO3A genotype is strongly associated with human longevity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 37 | pages = 13987–13992 | date = Sep 2008 | pmid = 18765803 | doi = 10.1073/pnas.0801030105 }}</ref>


=== Cancer ===
=== Cancer ===


Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation.<ref>{{vcite2 journal | vauthors = Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R | title = PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer | journal = Science | volume = 275 | issue = 5308 | pages = 1943–1947 | date = Mar 1997 | pmid = 9072974 }}</ref><ref>{{vcite2 journal | vauthors = Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE | title = High frequency of mutations of the PIK3CA gene in human cancers | journal = Science | volume = 304 | issue = 5670 | pages = 554 | date = Apr 2004 | pmid = 15016963 | doi = 10.1126/science.1096502 }}</ref><ref>{{vcite2 journal | vauthors = Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmström PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R | title = PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma | journal = Cancer Research | volume = 65 | issue = 7 | pages = 2554– 2559 | date = Apr 2005 | pmid = 15805248 | doi = 10.1158/0008-5472-CAN-04-3913 }}</ref> FOXO4 activates the cell cycle dependent kinase inhibitor, [[P27 (gene)|P27]], which in turn prevents tumors from progressing into [[Cell cycle checkpoint|G1]].<ref name = "Yang_2005">{{vcite2 journal | vauthors = Yang H, Zhao R, Yang HY, Lee MH | title = Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity | journal = Oncogene | volume = 24 | issue = 11 | pages = 1924–35 | date = Mar 2005 | pmid = 15688030 | doi = 10.1038/sj.onc.1208352 }}</ref> In [[HER-2]] positive tumor cells, increasing FOXO4 activity reduces tumor size.<ref name = "Yang_2005"/> Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia.<ref name = "Paik_2007" >{{vcite2 journal | vauthors = Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA | title = FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis | journal = Cell | volume = 128 | issue = 2 | pages = 309–323 | date = Jan 2007 | pmid = 17254969 | doi = 10.1016/j.cell.2006.12.029 }}</ref> The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.<ref name = "Paik_2007" />
Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation.<ref>{{cite journal | vauthors = Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R | title = PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer | journal = Science | volume = 275 | issue = 5308 | pages = 1943–1947 | date = Mar 1997 | pmid = 9072974 }}</ref><ref>{{cite journal | vauthors = Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE | title = High frequency of mutations of the PIK3CA gene in human cancers | journal = Science | volume = 304 | issue = 5670 | pages = 554 | date = Apr 2004 | pmid = 15016963 | doi = 10.1126/science.1096502 }}</ref><ref>{{cite journal | vauthors = Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmström PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R | title = PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma | journal = Cancer Research | volume = 65 | issue = 7 | pages = 2554– 2559 | date = Apr 2005 | pmid = 15805248 | doi = 10.1158/0008-5472-CAN-04-3913 }}</ref> FOXO4 activates the cell cycle dependent kinase inhibitor, [[P27 (gene)|P27]], which in turn prevents tumors from progressing into [[Cell cycle checkpoint|G1]].<ref name = "Yang_2005">{{cite journal | vauthors = Yang H, Zhao R, Yang HY, Lee MH | title = Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity | journal = Oncogene | volume = 24 | issue = 11 | pages = 1924–35 | date = Mar 2005 | pmid = 15688030 | doi = 10.1038/sj.onc.1208352 }}</ref> In [[HER-2]] positive tumor cells, increasing FOXO4 activity reduces tumor size.<ref name = "Yang_2005"/> Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia.<ref name = "Paik_2007" >{{cite journal | vauthors = Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA | title = FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis | journal = Cell | volume = 128 | issue = 2 | pages = 309–323 | date = Jan 2007 | pmid = 17254969 | doi = 10.1016/j.cell.2006.12.029 }}</ref> The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.<ref name = "Paik_2007" />


In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ.<ref>{{vcite2 journal | vauthors = Liu X, Zhang Z, Sun L, Chai N, Tang S, Jin J, Hu H, Nie Y, Wang X, Wu K, Jin H, Fan D | title = MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4 | journal = Carcinogenesis | volume = 32 | issue = 12 | pages = 1798–1805 | date = Dec 2011 | pmid = 21934092 | doi = 10.1093/carcin/bgr213 }}</ref> When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4’s function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis through upregulating [[vimentin]].<ref>{{vcite2 journal | vauthors = Su L, Liu X, Chai N, Lv L, Wang R, Li X, Nie Y, Shi Y, Fan D | title = The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer | journal = BMC Cancer | volume = 14 | pages = 378 | pmid = 24886657 | doi = 10.1186/1471-2407-14-378 }}</ref> These results are consistent with FOXO4 providing a role in inhibiting the [[Epithelial–mesenchymal transition|epithelia to mesenchymal transition]] (EMT).
In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ.<ref>{{cite journal | vauthors = Liu X, Zhang Z, Sun L, Chai N, Tang S, Jin J, Hu H, Nie Y, Wang X, Wu K, Jin H, Fan D | title = MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4 | journal = Carcinogenesis | volume = 32 | issue = 12 | pages = 1798–1805 | date = Dec 2011 | pmid = 21934092 | doi = 10.1093/carcin/bgr213 }}</ref> When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4’s function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis through upregulating [[vimentin]].<ref>{{cite journal | vauthors = Su L, Liu X, Chai N, Lv L, Wang R, Li X, Nie Y, Shi Y, Fan D | title = The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer | journal = BMC Cancer | volume = 14 | pages = 378 | pmid = 24886657 | doi = 10.1186/1471-2407-14-378 }}</ref> These results are consistent with FOXO4 providing a role in inhibiting the [[Epithelial–mesenchymal transition|epithelia to mesenchymal transition]] (EMT).


In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4.<ref name = "Xu_2014">{{vcite2 journal | vauthors = Xu MM, Mao GX, Liu J, Li JC, Huang H, Liu YF, Liu JH | title = Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer | journal = Asian Pacific Journal of Cancer Prevention | volume = 15 | issue = 9 | pages = 4013–4018 | pmid = 24935588 }}</ref> As with gastric cancer, these cancers with the lowest levels of FOXO4 also had the lowest levels of [[E-cadherin]] and highest levels of vimentin, consistent with FOXO4 acting as a suppressor of the EMT phenotype.<ref name = "Xu_2014"/>
In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4.<ref name = "Xu_2014">{{cite journal | vauthors = Xu MM, Mao GX, Liu J, Li JC, Huang H, Liu YF, Liu JH | title = Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer | journal = Asian Pacific Journal of Cancer Prevention | volume = 15 | issue = 9 | pages = 4013–4018 | pmid = 24935588 }}</ref> As with gastric cancer, these cancers with the lowest levels of FOXO4 also had the lowest levels of [[E-cadherin]] and highest levels of vimentin, consistent with FOXO4 acting as a suppressor of the EMT phenotype.<ref name = "Xu_2014"/>


== Interactions ==
== Interactions ==


FOXO4 has been shown to [[Protein-protein interaction|interact]] with [[PIN1]]<ref name=pmid18794148>{{vcite2 journal | vauthors = Brenkman AB, de Keizer PL, van den Broek NJ, van der Groep P, van Diest PJ, van der Horst A, Smits AM, Burgering BM | title = The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors | journal = Cancer Res. | volume = 68 | issue = 18 | pages = 7597–605 | date = Sep 2008 | pmid = 18794148 | doi = 10.1158/0008-5472.CAN-08-1059 }}</ref> and [[Mdm2]].<ref name=pmid18665269>{{vcite2 journal | vauthors = Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM | title = Mdm2 induces mono-ubiquitination of FOXO4 | journal = PLoS ONE | volume = 3 | issue = 7 | pages = e2819 | year = 2008 | pmid = 18665269 | pmc = 2475507 | doi = 10.1371/journal.pone.0002819 | editor1-last = Cookson | editor1-first = Mark R. }}</ref>
FOXO4 has been shown to [[Protein-protein interaction|interact]] with [[PIN1]]<ref name=pmid18794148>{{cite journal | vauthors = Brenkman AB, de Keizer PL, van den Broek NJ, van der Groep P, van Diest PJ, van der Horst A, Smits AM, Burgering BM | title = The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors | journal = Cancer Res. | volume = 68 | issue = 18 | pages = 7597–605 | date = Sep 2008 | pmid = 18794148 | doi = 10.1158/0008-5472.CAN-08-1059 }}</ref> and [[Mdm2]].<ref name=pmid18665269>{{cite journal | vauthors = Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM | title = Mdm2 induces mono-ubiquitination of FOXO4 | journal = PLoS ONE | volume = 3 | issue = 7 | pages = e2819 | year = 2008 | pmid = 18665269 | pmc = 2475507 | doi = 10.1371/journal.pone.0002819 | editor1-last = Cookson | editor1-first = Mark R. }}</ref>


== See also ==
== See also ==
Line 32: Line 32:
== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|33em}}
* {{vcite2 journal | vauthors = Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J, Henn T, Lampert F | title = Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23) | journal = Oncogene | volume = 14 | issue = 2 | pages = 195–202 | year = 1997 | pmid = 9010221 | doi = 10.1038/sj.onc.1200814 }}
* {{cite journal | vauthors = Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J, Henn T, Lampert F | title = Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23) | journal = Oncogene | volume = 14 | issue = 2 | pages = 195–202 | year = 1997 | pmid = 9010221 | doi = 10.1038/sj.onc.1200814 }}
* {{vcite2 journal | vauthors = Peters U, Haberhausen G, Kostrzewa M, Nolte D, Müller U | title = AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism | journal = Hum. Genet. | volume = 100 | issue = 5-6 | pages = 569–72 | year = 1997 | pmid = 9341872 | doi = 10.1007/s004390050553 }}
* {{cite journal | vauthors = Peters U, Haberhausen G, Kostrzewa M, Nolte D, Müller U | title = AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism | journal = Hum. Genet. | volume = 100 | issue = 5-6 | pages = 569–72 | year = 1997 | pmid = 9341872 | doi = 10.1007/s004390050553 }}
* {{vcite2 journal | vauthors = Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM | title = Direct control of the Forkhead transcription factor AFX by protein kinase B | journal = Nature | volume = 398 | issue = 6728 | pages = 630–4 | year = 1999 | pmid = 10217147 | doi = 10.1038/19328 }}
* {{cite journal | vauthors = Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM | title = Direct control of the Forkhead transcription factor AFX by protein kinase B | journal = Nature | volume = 398 | issue = 6728 | pages = 630–4 | year = 1999 | pmid = 10217147 | doi = 10.1038/19328 }}
* {{vcite2 journal | vauthors = Takaishi H, Konishi H, Matsuzaki H, Ono Y, Shirai Y, Saito N, Kitamura T, Ogawa W, Kasuga M, Kikkawa U, Nishizuka Y | title = Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 21 | pages = 11836–41 | year = 1999 | pmid = 10518537 | pmc = 18373 | doi = 10.1073/pnas.96.21.11836 }}
* {{cite journal | vauthors = Takaishi H, Konishi H, Matsuzaki H, Ono Y, Shirai Y, Saito N, Kitamura T, Ogawa W, Kasuga M, Kikkawa U, Nishizuka Y | title = Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 21 | pages = 11836–41 | year = 1999 | pmid = 10518537 | pmc = 18373 | doi = 10.1073/pnas.96.21.11836 }}
* {{vcite2 journal | vauthors = Medema RH, Kops GJ, Bos JL, Burgering BM | title = AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1 | journal = Nature | volume = 404 | issue = 6779 | pages = 782–7 | year = 2000 | pmid = 10783894 | doi = 10.1038/35008115 }}
* {{cite journal | vauthors = Medema RH, Kops GJ, Bos JL, Burgering BM | title = AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1 | journal = Nature | volume = 404 | issue = 6779 | pages = 782–7 | year = 2000 | pmid = 10783894 | doi = 10.1038/35008115 }}
* {{vcite2 journal | vauthors = Furuyama T, Nakazawa T, Nakano I, Mori N | title = Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues | journal = Biochem. J. | volume = 349 | issue = Pt 2 | pages = 629–34 | year = 2000 | pmid = 10880363 | pmc = 1221187 | doi = 10.1042/0264-6021:3490629 }}
* {{cite journal | vauthors = Furuyama T, Nakazawa T, Nakano I, Mori N | title = Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues | journal = Biochem. J. | volume = 349 | issue = Pt 2 | pages = 629–34 | year = 2000 | pmid = 10880363 | pmc = 1221187 | doi = 10.1042/0264-6021:3490629 }}
* {{vcite2 journal | vauthors = Weigelt J, Climent I, Dahlman-Wright K, Wikström M | title = 1H, 13C and 15N resonance assignments of the DNA binding domain of the human forkhead transcription factor AFX | journal = J. Biomol. NMR | volume = 17 | issue = 2 | pages = 181–2 | year = 2000 | pmid = 10921784 | doi = 10.1023/A:1008358816478 }}
* {{cite journal | vauthors = Weigelt J, Climent I, Dahlman-Wright K, Wikström M | title = 1H, 13C and 15N resonance assignments of the DNA binding domain of the human forkhead transcription factor AFX | journal = J. Biomol. NMR | volume = 17 | issue = 2 | pages = 181–2 | year = 2000 | pmid = 10921784 | doi = 10.1023/A:1008358816478 }}
* {{vcite2 journal | vauthors = Nasrin N, Ogg S, Cahill CM, Biggs W, Nui S, Dore J, Calvo D, Shi Y, Ruvkun G, Alexander-Bridges MC | title = DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 19 | pages = 10412–7 | year = 2000 | pmid = 10973497 | pmc = 27038 | doi = 10.1073/pnas.190326997 }}
* {{cite journal | vauthors = Nasrin N, Ogg S, Cahill CM, Biggs W, Nui S, Dore J, Calvo D, Shi Y, Ruvkun G, Alexander-Bridges MC | title = DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 19 | pages = 10412–7 | year = 2000 | pmid = 10973497 | pmc = 27038 | doi = 10.1073/pnas.190326997 }}
* {{vcite2 journal | vauthors = Brownawell AM, Kops GJ, Macara IG, Burgering BM | title = Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX | journal = Mol. Cell. Biol. | volume = 21 | issue = 10 | pages = 3534–46 | year = 2001 | pmid = 11313479 | pmc = 100275 | doi = 10.1128/MCB.21.10.3534-3546.2001 }}
* {{cite journal | vauthors = Brownawell AM, Kops GJ, Macara IG, Burgering BM | title = Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX | journal = Mol. Cell. Biol. | volume = 21 | issue = 10 | pages = 3534–46 | year = 2001 | pmid = 11313479 | pmc = 100275 | doi = 10.1128/MCB.21.10.3534-3546.2001 }}
* {{vcite2 journal | vauthors = Weigelt J, Climent I, Dahlman-Wright K, Wikström M | title = Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4) | journal = Biochemistry | volume = 40 | issue = 20 | pages = 5861–9 | year = 2001 | pmid = 11352721 | doi = 10.1021/bi001663w }}
* {{cite journal | vauthors = Weigelt J, Climent I, Dahlman-Wright K, Wikström M | title = Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4) | journal = Biochemistry | volume = 40 | issue = 20 | pages = 5861–9 | year = 2001 | pmid = 11352721 | doi = 10.1021/bi001663w }}
* {{vcite2 journal | vauthors = Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ | title = Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family | journal = J. Biol. Chem. | volume = 276 | issue = 36 | pages = 33554–60 | year = 2001 | pmid = 11435445 | doi = 10.1074/jbc.M105555200 }}
* {{cite journal | vauthors = Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ | title = Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family | journal = J. Biol. Chem. | volume = 276 | issue = 36 | pages = 33554–60 | year = 2001 | pmid = 11435445 | doi = 10.1074/jbc.M105555200 }}
* {{vcite2 journal | vauthors = De Ruiter ND, Burgering BM, Bos JL | title = Regulation of the Forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451 | journal = Mol. Cell. Biol. | volume = 21 | issue = 23 | pages = 8225–35 | year = 2001 | pmid = 11689711 | pmc = 99987 | doi = 10.1128/MCB.21.23.8225-8235.2001 }}
* {{cite journal | vauthors = De Ruiter ND, Burgering BM, Bos JL | title = Regulation of the Forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451 | journal = Mol. Cell. Biol. | volume = 21 | issue = 23 | pages = 8225–35 | year = 2001 | pmid = 11689711 | pmc = 99987 | doi = 10.1128/MCB.21.23.8225-8235.2001 }}
* {{vcite2 journal | vauthors = Tang TT, Dowbenko D, Jackson A, Toney L, Lewin DA, Dent AL, Lasky LA | title = The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor | journal = J. Biol. Chem. | volume = 277 | issue = 16 | pages = 14255–65 | year = 2002 | pmid = 11777915 | doi = 10.1074/jbc.M110901200 }}
* {{cite journal | vauthors = Tang TT, Dowbenko D, Jackson A, Toney L, Lewin DA, Dent AL, Lasky LA | title = The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor | journal = J. Biol. Chem. | volume = 277 | issue = 16 | pages = 14255–65 | year = 2002 | pmid = 11777915 | doi = 10.1074/jbc.M110901200 }}
* {{vcite2 journal | vauthors = Yang Z, Whelan J, Babb R, Bowen BR | title = An mRNA splice variant of the AFX gene with altered transcriptional activity | journal = J. Biol. Chem. | volume = 277 | issue = 10 | pages = 8068–75 | year = 2002 | pmid = 11779849 | doi = 10.1074/jbc.M106091200 }}
* {{cite journal | vauthors = Yang Z, Whelan J, Babb R, Bowen BR | title = An mRNA splice variant of the AFX gene with altered transcriptional activity | journal = J. Biol. Chem. | volume = 277 | issue = 10 | pages = 8068–75 | year = 2002 | pmid = 11779849 | doi = 10.1074/jbc.M106091200 }}
* {{vcite2 journal | vauthors = Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, Lam EW, Burgering BM | title = Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors | journal = Mol. Cell. Biol. | volume = 22 | issue = 7 | pages = 2025–36 | year = 2002 | pmid = 11884591 | pmc = 133681 | doi = 10.1128/MCB.22.7.2025-2036.2002 }}
* {{cite journal | vauthors = Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, Lam EW, Burgering BM | title = Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors | journal = Mol. Cell. Biol. | volume = 22 | issue = 7 | pages = 2025–36 | year = 2002 | pmid = 11884591 | pmc = 133681 | doi = 10.1128/MCB.22.7.2025-2036.2002 }}
* {{vcite2 journal | vauthors = So CW, Cleary ML | title = MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function | journal = Mol. Cell. Biol. | volume = 22 | issue = 18 | pages = 6542–52 | year = 2002 | pmid = 12192052 | pmc = 135648 | doi = 10.1128/MCB.22.18.6542-6552.2002 }}
* {{cite journal | vauthors = So CW, Cleary ML | title = MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function | journal = Mol. Cell. Biol. | volume = 22 | issue = 18 | pages = 6542–52 | year = 2002 | pmid = 12192052 | pmc = 135648 | doi = 10.1128/MCB.22.18.6542-6552.2002 }}
* {{vcite2 journal | vauthors = Tang TT, Lasky LA | title = The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism | journal = J. Biol. Chem. | volume = 278 | issue = 32 | pages = 30125–35 | year = 2003 | pmid = 12761217 | doi = 10.1074/jbc.M302042200 }}
* {{cite journal | vauthors = Tang TT, Lasky LA | title = The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism | journal = J. Biol. Chem. | volume = 278 | issue = 32 | pages = 30125–35 | year = 2003 | pmid = 12761217 | doi = 10.1074/jbc.M302042200 }}
* {{vcite2 journal | vauthors = Crossley LJ | title = Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1 | journal = J. Leukoc. Biol. | volume = 74 | issue = 4 | pages = 583–92 | year = 2003 | pmid = 12960271 | doi = 10.1189/jlb.0103020 }}
* {{cite journal | vauthors = Crossley LJ | title = Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1 | journal = J. Leukoc. Biol. | volume = 74 | issue = 4 | pages = 583–92 | year = 2003 | pmid = 12960271 | doi = 10.1189/jlb.0103020 }}
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Revision as of 09:34, 2 August 2015

Template:PBB Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.[1][2] It is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533.[3]

Structure and function

FOXO4 is a member of the forkhead family transciption factors O subclass, which is characterized by a winged helix domain used for DNA binding.[4][5] There are 4 members of the FOXO family, including FOXO1, FOXO3, and FOXO6. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation.[6] Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis.[7][8][9][10][11] Two of the main upstream regulators of FOXO4 activity is phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB.[12][13] Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.

Clinical significance

Associations with longevity

FOXO transcription factors have been shown to be the down downstream effector molecules of insulin-like growth factor (IGF) signaling pathway. In the absence of insulin, PI3K is inactive so FOXO is able to translocate to the nucleus and turn on many genetic pathways associated with longevity.[14] FOXO’s ability to restrict this pathway produces an increase in lifespan for worms, flies, mice, and correlates to longer human lives as well.[15][16]

Cancer

Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation.[17][18][19] FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1.[20] In HER-2 positive tumor cells, increasing FOXO4 activity reduces tumor size.[20] Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia.[21] The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.[21]

In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ.[22] When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4’s function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis through upregulating vimentin.[23] These results are consistent with FOXO4 providing a role in inhibiting the epithelia to mesenchymal transition (EMT).

In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4.[24] As with gastric cancer, these cancers with the lowest levels of FOXO4 also had the lowest levels of E-cadherin and highest levels of vimentin, consistent with FOXO4 acting as a suppressor of the EMT phenotype.[24]

Interactions

FOXO4 has been shown to interact with PIN1[25] and Mdm2.[26]

See also

References

  1. ^ Parry P, Wei Y, Evans G (Feb 1995). "Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family". Genes Chromosomes Cancer. 11 (2): 79–84. doi:10.1002/gcc.2870110203. PMID 7529552.
  2. ^ "Entrez Gene: MLLT7 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 7".
  3. ^ http://ghr.nlm.nih.gov/gene/FOXO4#location
  4. ^ Weigel D, Jäckle H (Nov 1990). "The fork head domain: a novel DNA binding motif of eukaryotic transcription factors?". Cell. 63 (3): 455–456. PMID 2225060.
  5. ^ Kaestner KH, Knochel W, Martinez DE (Jan 2000). "Unified nomenclature for the winged helix/forkhead transcription factors". Genes & Development. 14 (2): 142–146. PMID 10702024.
  6. ^ van der Horst A, Burgering BM (Jun 2007). "Stressing the role of FoxO proteins in lifespan and disease". Nature Reviews. Molecular Cell Biology. 8 (6): 440–450. doi:10.1038/nrm2190. PMID 17522590.
  7. ^ van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP (Nov 2005). "FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling". The Biochemical Journal. 391 (Pt 3): 623–629. doi:10.1042/BJ20050525. PMID 15987244.
  8. ^ Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A (Aug 2005). "Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation". Proceedings of the National Academy of Sciences of the United States of America. 102 (32): 11278–11283. doi:10.1073/pnas.0502738102. PMID 16076959.
  9. ^ Boura E, Silhan J, Herman P, Vecer J, Sulc M, Teisinger J, Obsilova V, Obsil T (Mar 2007). "Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding". The Journal of Biological Chemistry. 282 (11): 8265–8275. doi:10.1074/jbc.M605682200. PMID 17244620.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD. "Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification". Nucleic Acids Research. 35 (20): 6984–6994. doi:10.1093/nar/gkm703. PMID 17940099.
  11. ^ : 1407–1416. PMID 18786403. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
  12. ^ Manning BD, Cantley LC (Jun 2007). "AKT/PKB signaling: navigating downstream". Cell. 129 (7): 261–1274. doi:10.1016/j.cell.2007.06.009. PMID 17604717.
  13. ^ Calnan DR, Brunet A (Apr 2008). "The FoxO code". Oncogene. 27 (16): 2276–2288. doi:10.1038/onc.2008.21. PMID 18391970.
  14. ^ Neumann-Haefelin E, Qi W, Finkbeiner E, Walz G, Baumeister R, Hertweck M (Oct 2008). "SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans". Genes & Development. 22 (19): 2721–2735. doi:10.1101/gad.478408. PMID 18832074.
  15. ^ Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (Dec 1993). "A C. elegans mutant that lives twice as long as wild type". Nature. 366 (6454): 461–464. doi:10.1038/366461a0. PMID 8247153.
  16. ^ Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (Sep 2008). "FOXO3A genotype is strongly associated with human longevity". Proceedings of the National Academy of Sciences of the United States of America. 105 (37): 13987–13992. doi:10.1073/pnas.0801030105. PMID 18765803.
  17. ^ Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (Mar 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science. 275 (5308): 1943–1947. PMID 9072974.
  18. ^ Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (Apr 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science. 304 (5670): 554. doi:10.1126/science.1096502. PMID 15016963.
  19. ^ Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmström PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R (Apr 2005). "PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma". Cancer Research. 65 (7): 2554–2559. doi:10.1158/0008-5472-CAN-04-3913. PMID 15805248.
  20. ^ a b Yang H, Zhao R, Yang HY, Lee MH (Mar 2005). "Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity". Oncogene. 24 (11): 1924–35. doi:10.1038/sj.onc.1208352. PMID 15688030.
  21. ^ a b Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA (Jan 2007). "FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis". Cell. 128 (2): 309–323. doi:10.1016/j.cell.2006.12.029. PMID 17254969.
  22. ^ Liu X, Zhang Z, Sun L, Chai N, Tang S, Jin J, Hu H, Nie Y, Wang X, Wu K, Jin H, Fan D (Dec 2011). "MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4". Carcinogenesis. 32 (12): 1798–1805. doi:10.1093/carcin/bgr213. PMID 21934092.
  23. ^ Su L, Liu X, Chai N, Lv L, Wang R, Li X, Nie Y, Shi Y, Fan D. "The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer". BMC Cancer. 14: 378. doi:10.1186/1471-2407-14-378. PMID 24886657.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ a b Xu MM, Mao GX, Liu J, Li JC, Huang H, Liu YF, Liu JH. "Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer". Asian Pacific Journal of Cancer Prevention. 15 (9): 4013–4018. PMID 24935588.
  25. ^ Brenkman AB, de Keizer PL, van den Broek NJ, van der Groep P, van Diest PJ, van der Horst A, Smits AM, Burgering BM (Sep 2008). "The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors". Cancer Res. 68 (18): 7597–605. doi:10.1158/0008-5472.CAN-08-1059. PMID 18794148.
  26. ^ Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM (2008). Cookson MR (ed.). "Mdm2 induces mono-ubiquitination of FOXO4". PLoS ONE. 3 (7): e2819. doi:10.1371/journal.pone.0002819. PMC 2475507. PMID 18665269.{{cite journal}}: CS1 maint: unflagged free DOI (link)

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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