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The expression of this gene is tightly controlled by the tumor suppressor protein [[p53]], through which this protein mediates the p53-dependent cell cycle G<sub>1</sub> phase arrest in response to a variety of stress stimuli.<ref name="pmid16280359">{{vcite2 journal | vauthors = Rodriguez R, Meuth M | title = Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress | journal = Mol. Biol. Cell | volume = 17 | issue = 1 | pages = 402-12 | year = 2006 | date = January 2006 | pmid = 16280359 | pmc = 1345677 | doi = 10.1091/mbc.E05-07-0594 }}</ref> This was a major discovery in the early 1990s that revealed how cells stop dividing after being exposed to damaging agents such as radiation.
The expression of this gene is tightly controlled by the tumor suppressor protein [[p53]], through which this protein mediates the p53-dependent cell cycle G<sub>1</sub> phase arrest in response to a variety of stress stimuli.<ref name="pmid16280359">{{vcite2 journal | vauthors = Rodriguez R, Meuth M | title = Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress | journal = Mol. Biol. Cell | volume = 17 | issue = 1 | pages = 402-12 | year = 2006 | date = January 2006 | pmid = 16280359 | pmc = 1345677 | doi = 10.1091/mbc.E05-07-0594 }}</ref> This was a major discovery in the early 1990s that revealed how cells stop dividing after being exposed to damaging agents such as radiation.


Studies of human embryonic stem cells (hESCs) commonly report the nonfunctional p53-p21 axis of the G1/S checkpoint pathway, and its relevance for cell cycle regulation and the DNA damage response (DDR). p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.<ref>{{vvcite2 journal | vauthors = Dolezalova D, Mraz M, Barta T, Plevova K, Vinarsky V, Holubcova Z, Jaros J, Dvorak P, Pospisilova S, Hampl A. | title = MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells. | journal = Stem Cells | volume = 7 | pages = 1362-72.| year = 2012 | doi = 10.1002/stem.1108.| pmid = 22511267 |}}</ref>
Studies of human embryonic stem cells (hESCs) commonly report the nonfunctional p53-p21 axis of the G1/S checkpoint pathway, and its relevance for cell cycle regulation and the DNA damage response (DDR). p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.<ref>{{vcite2 journal | vauthors = Dolezalova D, Mraz M, Barta T, Plevova K, Vinarsky V, Holubcova Z, Jaros J, Dvorak P, Pospisilova S, Hampl A. | title = MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells. | journal = Stem Cells | volume = 7 | pages = 1362-72.| year = 2012 | doi = 10.1002/stem.1108.| pmid = 22511267 |}}</ref>


p21 can also interact with proliferating cell nuclear antigen ([[PCNA]]), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. <ref name="pmid1358458">[http://www.ncbi.nlm.nih.gov/pubmed/1358458], Xiong Y, Zhang H, Beach D. (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell Oct 30;71(3):505-14.</ref> This protein was reported to be specifically cleaved by [[CASP3]]-like [[caspase]]s, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of [[apoptosis]] following [[caspase]] activation. However p21 may inhibit apoptosis and does not induce cell death on its own.<ref name="pmid11960320">{{vcite2 journal | vauthors = Almond JB, Cohen GM | title = The proteasome: a novel target for cancer chemotherapy | journal = Leukemia | volume = 16 | issue = 4 | pages = 433-43 | year = 2002 | date = April 2002 | pmid = 11960320 | doi = 10.1038/sj.leu.2402417 }}</ref> Two alternatively spliced variants, which encode an identical protein, have been reported.
p21 can also interact with proliferating cell nuclear antigen ([[PCNA]]), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. <ref name="pmid1358458">[http://www.ncbi.nlm.nih.gov/pubmed/1358458], Xiong Y, Zhang H, Beach D. (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell Oct 30;71(3):505-14.</ref> This protein was reported to be specifically cleaved by [[CASP3]]-like [[caspase]]s, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of [[apoptosis]] following [[caspase]] activation. However p21 may inhibit apoptosis and does not induce cell death on its own.<ref name="pmid11960320">{{vcite2 journal | vauthors = Almond JB, Cohen GM | title = The proteasome: a novel target for cancer chemotherapy | journal = Leukemia | volume = 16 | issue = 4 | pages = 433-43 | year = 2002 | date = April 2002 | pmid = 11960320 | doi = 10.1038/sj.leu.2402417 }}</ref> Two alternatively spliced variants, which encode an identical protein, have been reported.

Revision as of 19:30, 24 January 2015

This article is about the p21/waf1 protein. For the p21/ras protein see Ras. For other uses, see P21 (disambiguation)

Template:PBB p21 / WAF1 / CIP1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 (6p21.2).[1][2][3][4]

Function

p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G1 and S phase.[5] In addition to growth arrest, p21 can mediate cellular senescence. One of the ways it was discovered was as a senescent cell-derived inhibitor.

The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli.[6] This was a major discovery in the early 1990s that revealed how cells stop dividing after being exposed to damaging agents such as radiation.

Studies of human embryonic stem cells (hESCs) commonly report the nonfunctional p53-p21 axis of the G1/S checkpoint pathway, and its relevance for cell cycle regulation and the DNA damage response (DDR). p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.[7]

p21 can also interact with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. [8] This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. However p21 may inhibit apoptosis and does not induce cell death on its own.[9] Two alternatively spliced variants, which encode an identical protein, have been reported.

Sometimes p21 is expressed without being induced by p53. This kind of induction plays a big role in p53 independent differentiation which is promoted by p21. Expression of p21 is mainly dependent on two factors 1) stimulus provided 2) type of the cell. Growth arrest by p21 can promote cellular differentiation. p21 therefore prevents cell proliferation.

Despite regulation by tumor suppressor gene p53, loss-of-function mutations in p21 (unlike p53) do not accumulate in cancer nor do they predispose to cancer incidence. Mice genetically engineered to lack p21 develop normally and are not susceptible to cancer at a higher rate than wild-type mice (unlike p53 knockout mice).

Mice that lack the p21 gene gain the ability to regenerate lost appendages.[10]

Clinical significance

p21 mediates the resistance of hematopoietic cells to an infection with HIV[11] by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus. HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA. p21 expression affects at least two stages in the HIV life cycle inside CD4 T cells, significantly limiting production of new viruses.[12]

Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.[13][14]

Interactions

P21 has been shown to interact with:

References

  1. ^ "Entrez Gene: CDKN1A cyclin-dependent kinase inhibitor 1A (p21, Cip1)".
  2. ^ a b Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (November 1993). "The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases". Cell. 75 (4): 805–16. doi:10.1016/0092-8674(93)90499-G. PMID 8242751.{{cite journal}}: CS1 maint: date and year (link)
  3. ^ el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (November 1993). "WAF1, a potential mediator of p53 tumor suppression". Cell. 75 (4): 817–25. doi:10.1016/0092-8674(93)90500-P. PMID 8242752.{{cite journal}}: CS1 maint: date and year (link)
  4. ^ [1], Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. (1993) p21 is a universal inhibitor of cyclin kinases. Nature 16;366(6456):701-4.
  5. ^ Gartel AL, Radhakrishnan SK (May 2005). "Lost in transcription: p21 repression, mechanisms, and consequences". Cancer Res. 65 (10): 3980–5. doi:10.1158/0008-5472.CAN-04-3995. PMID 15899785.{{cite journal}}: CS1 maint: date and year (link)
  6. ^ Rodriguez R, Meuth M (January 2006). "Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress". Mol. Biol. Cell. 17 (1): 402–12. doi:10.1091/mbc.E05-07-0594. PMC 1345677. PMID 16280359.{{cite journal}}: CS1 maint: date and year (link)
  7. ^ Dolezalova D, Mraz M, Barta T, Plevova K, Vinarsky V, Holubcova Z, Jaros J, Dvorak P, Pospisilova S, Hampl A. (2012). "MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells". Stem Cells. 7: 1362-72. doi:10.1002/stem.1108.. PMID 22511267. {{cite journal}}: Check |doi= value (help); Cite has empty unknown parameter: |1= (help); Vancouver style error: punctuation in name 10 (help)
  8. ^ [2], Xiong Y, Zhang H, Beach D. (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell Oct 30;71(3):505-14.
  9. ^ Almond JB, Cohen GM (April 2002). "The proteasome: a novel target for cancer chemotherapy". Leukemia. 16 (4): 433–43. doi:10.1038/sj.leu.2402417. PMID 11960320.{{cite journal}}: CS1 maint: date and year (link)
  10. ^ Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, Heber-Katz E (March 2010). "Lack of p21 expression links cell cycle control and appendage regeneration in mice". Proc. Natl. Acad. Sci. U.S.A. 107 (13): 5845–50. doi:10.1073/pnas.1000830107. PMC 2851923. PMID 20231440. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)CS1 maint: date and year (link)
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  15. ^ Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, Zhang DD (June 2009). "Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response". Mol. Cell. 34 (6): 663–73. doi:10.1016/j.molcel.2009.04.029. PMC 2714804. PMID 19560419.{{cite journal}}: CS1 maint: date and year (link)
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Further reading

  • Marone M, Bonanno G, Rutella S, Leone G, Scambia G, Pierelli L (2002). "Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21". Leuk. Lymphoma. 43 (1): 51–7. doi:10.1080/10428190210195. PMID 11908736.
  • Fang JY, Lu YY (2002). "Effects of histone acetylation and DNA methylation on p21( WAF1) regulation". World J. Gastroenterol. 8 (3): 400–5. PMID 12046058.
  • Tokumoto M, Tsuruya K, Fukuda K, Kanai H, Kuroki S, Hirakata H, Iida M (2003). "Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27". Nephrol. Dial. Transplant. 18 Suppl 3: iii9-12. PMID 12771291.
  • Amini S, Khalili K, Sawaya BE (2004). "Effect of HIV-1 Vpr on cell cycle regulators". DNA Cell Biol. 23 (4): 249–60. doi:10.1089/104454904773819833. PMID 15142382.
  • Zhang Z, Wang H, Li M, Rayburn E, Agrawal S, Zhang R (2005). "Novel MDM2 p53-independent functions identified through RNA silencing technologies". Ann. N. Y. Acad. Sci. 1058: 205–14. doi:10.1196/annals.1359.030. PMID 16394138.
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