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{{PBB|geneid=10912}}
{{PBB|geneid=10912}}
'''Growth arrest and DNA-damage-inducible protein GADD45 gamma''' is a [[protein]] that in humans is encoded by the ''GADD45G'' [[gene]]. GADD45G is also known as CR6, DDIT2, GRP17 and GADD45gamma.<ref name="pmid10496071">{{cite journal | author = Suzuki M, Watanabe TK, Fujiwara T, Nakamura Yp6, Takahashi E, Tanigami A | title = Molecular cloning, expression, and mapping of a novel human cDNA, GRP17, highly homologous to human gadd45 and murine MyD118 | journal = J Hum Genet | volume = 44 | issue = 5 | pages = 300–3 |date=Oct 1999 | pmid = 10496071 | pmc = | doi = 10.1007/s100380050164 }}</ref>
'''Growth arrest and DNA-damage-inducible protein GADD45 gamma''' is a [[protein]] that in humans is encoded by the ''GADD45G'' [[gene]]. GADD45G is also known as CR6, DDIT2, GRP17 and GADD45gamma.<ref name="pmid10496071">{{cite journal | author = Suzuki M, Watanabe TK, Fujiwara T, Nakamura Yp6, Takahashi E, Tanigami A | title = Molecular cloning, expression, and mapping of a novel human cDNA, GRP17, highly homologous to human gadd45 and murine MyD118 | journal = J Hum Genet | volume = 44 | issue = 5 | pages = 300–3 |date=Oct 1999 | pmid = 10496071 | pmc = | doi = 10.1007/s100380050164 }}</ref> Gadd45g has several different functions, including sexual development<ref>{{cite journal |author=Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM |title=Gadd45g is essential for primary sex determination, male fertility and testis development |journal=PLoS ONE |volume=8 |issue=3 |pages=e58751 |year=2013 |pmid=23516551 |pmc=3596291 |doi=10.1371/journal.pone.0058751 |url=}}</ref>, human-specific brain development<ref>{{cite journal |author=McLean CY, Reno PL, Pollen AA, ''et al.'' |title=Human-specific loss of regulatory DNA and the evolution of human-specific traits |journal=Nature |volume=471 |issue=7337 |pages=216–9 |year=2011 |month=March |pmid=21390129 |pmc=3071156 |doi=10.1038/nature09774 |url=}}</ref>, tumor suppression<ref>{{cite journal |author=Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF |title=GADD45 proteins: central players in tumorigenesis |journal=Curr. Mol. Med. |volume=12 |issue=5 |pages=634–51 |year=2012 |month=June |pmid=22515981 |pmc=3797964 |doi= |url=}}</ref>, and the cellular stress response.<ref>{{cite journal |author=Liebermann DA, Hoffman B |title=Gadd45 in the response of hematopoietic cells to genotoxic stress |journal=Blood Cells Mol. Dis. |volume=39 |issue=3 |pages=329–35 |year=2007 |pmid=17659913 |pmc=3268059 |doi=10.1016/j.bcmd.2007.06.006 |url=}}</ref> Gadd45g interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence. <ref>{{cite journal |author=Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM |title=Gadd45g is essential for primary sex determination, male fertility and testis development |journal=PLoS ONE |volume=8 |issue=3 |pages=e58751 |year=2013 |pmid=23516551 |pmc=3596291 |doi=10.1371/journal.pone.0058751 |url=}}</ref> Low expression of GADD45G has been found to be involved in many types of cancer. <ref name="Zhang_2014">{{cite journal | author = Zhang L, Yang Z, Ma A, Qu Y, Xia S, Xu D, Ge C, Qiu B, Xia Q, Li J, Liu Y | title = Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma | journal = Hepatology | volume = 59 | issue = 1 | pages = 178–89 | year = 2014 | month = January | pmid = 23897841 | doi = 10.1002/hep.26628 }}</ref>


== Structure and Function ==
== Structure and Function ==

Revision as of 20:18, 18 March 2014

Template:PBB Growth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene. GADD45G is also known as CR6, DDIT2, GRP17 and GADD45gamma.[1] Gadd45g has several different functions, including sexual development[2], human-specific brain development[3], tumor suppression[4], and the cellular stress response.[5] Gadd45g interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence. [6] Low expression of GADD45G has been found to be involved in many types of cancer. [7]

Structure and Function

This gene is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The protein encoded by this gene responds to environmental stresses by mediating activation of the p38/JNK pathway via MTK1/MEKK4 kinase.[8] Gadd45g is in turn regulated upstream by NF-κB. [9]. The GADD45G is highly expressed in placenta.[10]

The crystal structure of GADD45G reveals a dimer made of four parallel helices. The central region contains a highly acidic patch where it allows for interaction with cdc2, PCNA, and p21. The parallel isoform of GADD45G is the active form.[11]

This gene plays a role in cell cycle regulation. GADD45G prevents the kinase ability of the cyclin b1/Cdk 1 complex in a fashion that does not break apart the complex. It plays a role in the activation of the S and G2/M checkpoints.[12] GADD45G must undergo dimerization in order for proper growth suppression and cell death.[11]

In the male sexual development pathway, Gadd45g is essential for activating SRY, leading to proper formation of the gonads and sex-determination. This could occur through Gadd45g interaction with the p38 MAPK signaling pathway. [13]

Deletion of an enhancer close to the Gadd45g gene is correlated to increased proliferation of neuronal cells, which could account for part of the difference in neural development between humans and other species. [14]

GADD45G is involved with dental epithelial cell proliferation. GADD45G is expressed in enamel knots, where it regulates gene expression and cell growth. The gene modulates p21-mediated epithelial cell proliferation by activating the p38 MAPK pathway during the development of teeth.[15]

Interactions

GADD45G has been shown to interact with:

Clinical significance

Generally, in numerous kinds of cancerous cells, GADD45G is down regulated.[7] There is a low expression due to methylation of the GADD45G promotor.[15] This low expression can also be explained by increased NF-κB activation. [19]

GADD45G methylation is seen in many cancers. In esophageal cancer the expression level and methylation status of the gene are involved in the prognosis of esophageal squamous cell carcinoma. Demethylation of the gene can have some beneficial effects.[15] GADD45G methylation levels are also measured in the diagnosis of pancreatic, gastric and colorectal cancers.[20]

In cancerous liver cells, GADD45G is down regulated.It participates in negatively regulating the Jak-Stat3 signaling pathway. It acts as a tumor suppressor in HCC cells by promoting cell death or growth arrest. When GADD45G expression is low, liver cells may be able to bypass the growth arrest stage, leading to cancerous cells.[7]

The presence of GADD45G in the urinary system is also related to renal disease. The renal cells expressing the gene where damaged.[21]

In the pituitary gland, GADD45G is a growth suppressor. There is a loss of expression of the gene in many pituitary cancerous masses.[22]

The gene plays a role in prostate cancer as a tumor supressor as well. In these cancerous cells, Vitamin D can induce the expression of GADD45G.[23]

Tissue distribution

GADD45G is expressed most in the skeletal muscle, kidney and liver. This gene has a low expression in the heart, brain, spleen, lung and testis.[24]

History

GADD45G was originally cloned by Beadling under the name CR6 in 1993 [25], and its function as a tumor suppressor was discovered in 1999 by Zhang. [26]

See also

References

  1. ^ Suzuki M, Watanabe TK, Fujiwara T, Nakamura Yp6, Takahashi E, Tanigami A (Oct 1999). "Molecular cloning, expression, and mapping of a novel human cDNA, GRP17, highly homologous to human gadd45 and murine MyD118". J Hum Genet. 44 (5): 300–3. doi:10.1007/s100380050164. PMID 10496071.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  2. ^ Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM (2013). "Gadd45g is essential for primary sex determination, male fertility and testis development". PLoS ONE. 8 (3): e58751. doi:10.1371/journal.pone.0058751. PMC 3596291. PMID 23516551.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  3. ^ McLean CY, Reno PL, Pollen AA; et al. (2011). "Human-specific loss of regulatory DNA and the evolution of human-specific traits". Nature. 471 (7337): 216–9. doi:10.1038/nature09774. PMC 3071156. PMID 21390129. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF (2012). "GADD45 proteins: central players in tumorigenesis". Curr. Mol. Med. 12 (5): 634–51. PMC 3797964. PMID 22515981. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Liebermann DA, Hoffman B (2007). "Gadd45 in the response of hematopoietic cells to genotoxic stress". Blood Cells Mol. Dis. 39 (3): 329–35. doi:10.1016/j.bcmd.2007.06.006. PMC 3268059. PMID 17659913.
  6. ^ Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM (2013). "Gadd45g is essential for primary sex determination, male fertility and testis development". PLoS ONE. 8 (3): e58751. doi:10.1371/journal.pone.0058751. PMC 3596291. PMID 23516551.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  7. ^ a b c Zhang L, Yang Z, Ma A, Qu Y, Xia S, Xu D, Ge C, Qiu B, Xia Q, Li J, Liu Y (2014). "Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma". Hepatology. 59 (1): 178–89. doi:10.1002/hep.26628. PMID 23897841. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ a b Takekawa M, Saito H (Dec 1998). "A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK". Cell. 95 (4): 521–30. doi:10.1016/S0092-8674(00)81619-0. PMID 9827804. Cite error: The named reference "pmid9827804" was defined multiple times with different content (see the help page).
  9. ^ Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF (2012). "GADD45 proteins: central players in tumorigenesis". Curr. Mol. Med. 12 (5): 634–51. PMC 3797964. PMID 22515981. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ "Entrez Gene: GADD45G growth arrest and DNA-damage-inducible, gamma".
  11. ^ a b Zhang W, Fu S, Liu X, Zhao X, Zhang W, Peng W; et al. (2011). "Crystal structure of human Gadd45γ [corrected] reveals an active dimer". Protein Cell. 2 (10): 814–26. doi:10.1007/s13238-011-1090-6. PMID 22058036. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  12. ^ a b c Vairapandi M, Balliet AG, Hoffman B, Liebermann DA (2002). "GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress". J. Cell. Physiol. 192 (3): 327–38. doi:10.1002/jcp.10140. PMID 12124778. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM (2013). "Gadd45g is essential for primary sex determination, male fertility and testis development". PLoS ONE. 8 (3): e58751. doi:10.1371/journal.pone.0058751. PMC 3596291. PMID 23516551.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  14. ^ McLean CY, Reno PL, Pollen AA; et al. (2011). "Human-specific loss of regulatory DNA and the evolution of human-specific traits". Nature. 471 (7337): 216–9. doi:10.1038/nature09774. PMC 3071156. PMID 21390129. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ a b c Ishida K, Yuge Y, Hanaoka M, Yasukawa M, Minami Y, Ogawa M, Masumoto KH, Shigeyoshi Y, Saito M, Tsuji T (2013). "Gadd45g regulates dental epithelial cell proliferation through p38 MAPK-mediated p21 expression". Genes Cells. 18 (8): 660–71. doi:10.1111/gtc.12067. PMID 23751077. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ a b Chung HK, Yi YW, Jung NC, Kim D, Suh JM, Kim H, Park KC, Song JH, Kim DW, Hwang ES, Yoon SH, Bae YS, Kim JM, Bae I, Shong M (Jul 2003). "CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle". J. Biol. Chem. 278 (30): 28079–88. doi:10.1074/jbc.M212835200. PMID 12716909.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  17. ^ a b Azam N, Vairapandi M, Zhang W, Hoffman B, Liebermann DA (Jan 2001). "Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control". J. Biol. Chem. 276 (4): 2766–74. doi:10.1074/jbc.M005626200. PMID 11022036.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  18. ^ a b Nakayama K, Hara T, Hibi M, Hirano T, Miyajima A (Aug 1999). "A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth". J. Biol. Chem. 274 (35): 24766–72. PMID 10455148.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Dan A. Liebermann, Jennifer S. Tront, Xiogen Sha, Ksushiki Mukherjee, Alisha Mohamed-Hadley & Barbara Hoffman (2011). "Gadd45 stress sensors in malignancy and leukemia". Critical reviews in oncogenesis. 16 (1–2): 129–140. PMID 22150313. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
  20. ^ Zhang W, Li T, Shao Y, Zhang C, Wu Q, Yang H; et al. (2010). "Semi-quantitative detection of GADD45-gamma methylation levels in gastric, colorectal and pancreatic cancers using methylation-sensitive high-resolution melting analysis". J Cancer Res Clin Oncol. 136 (8): 1267–73. doi:10.1007/s00432-010-0777-z. PMID 20111973. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  21. ^ Yu S, Cho J, Park I, Kim SJ, Kim H, Shin GT (2009). "Urinary GADD45gamma expression is associated with progression of lgA nephropathy". Am J Nephrol. 30 (2): 135–9. doi:10.1159/000209317. PMID 19293565.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Zhang X, Sun H, Danila DC, Johnson SR, Zhou Y, Swearingen B; et al. (2002). "Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis". J Clin Endocrinol Metab. 87 (3): 1262–7. doi:10.1210/jcem.87.3.8315. PMID 11889197. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  23. ^ Flores O, Burnstein KL (2010). "GADD45gamma: a new vitamin D-regulated gene that is antiproliferative in prostate cancer cells". Endocrinology. 151 (10): 4654–64. doi:10.1210/en.2010-0434. PMC 2946153. PMID 20739400.{{cite journal}}: CS1 maint: PMC format (link)
  24. ^ Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF (June 2012). "GADD45 proteins: central players in tumorigenesis". Curr. Mol. Med. 12 (5): 634–51. PMC 3797964. PMID 22515981.
  25. ^ C. Beadling, K. W. Johnson & K. A. Smith (1993). "Isolation of interleukin 2-induced immediate-early genes". Proceedings of the National Academy of Sciences of the United States of America. 90 (7): 2719–2723. PMID 7681987. {{cite journal}}: Unknown parameter |month= ignored (help)
  26. ^ W. Zhang, I. Bae, K. Krishnaraju, N. Azam, W. Fan, K. Smith, B. Hoffman & D. A. Liebermann (1999). "CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control". Oncogene. 18 (35): 4899–4907. doi:10.1038/sj.onc.1202885. PMID 10490824. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

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