p53 pp 100-116 | Cite as

Regulation and Function of the Original p53- Inducible p21 Gene

  • Jennifer A. Fraser
Part of the Molecular Biology Intelligence Unit book series (MBIU, volume 1)

Abstract

P21 is a well known regulator of cell cycle progression through its inhibitory actions on Cyclin dependent kinases, (Cdk)/cyclin complexes, and DNA replication via its binding to proliferating cell nuclear antigen (PCNA). p21 also has a role in many diverse cellular processes including modulation of apoptosis, regulation of Rho Kinase and modification of cytoskeletal structures, as well as cellular senescence and differentiation.1–6 Due to its multiple and wide ranging effects on key cellular processes, intracellular p21 levels are tightly regulated. p53 is a major transcriptional regulator of p21, and p53-dependent transcription of p21 in response to DNA damage is well characterized. However, p53-independent transcriptional pathways also exist.7 More recently, post-translational mechanisms that influence p21 steady state levels have been identified, including modulation of p21 binding interactions, phosphorylation status, subcellular localization, and trafficking to the proteasome. Post-translational regulation of p21, particularly at its COOH terminus has a significant impact on p21 stability and abundance and therefore is an important determinant of intracellular p21 concentration.

Keywords

Lysine Polypeptide Arginine Caffeine Half Life 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Besson A, Assoian RK, Roberts JM. Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors? Nat Rev Cancer 2004; 4:948–955.PubMedCrossRefGoogle Scholar
  2. 2.
    Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell 2008; 14:159–169.PubMedCrossRefGoogle Scholar
  3. 3.
    Denicourt C, Dowdy SF. Cip/Kip proteins: more than just CDKs inhibitors. Genes Dev 2004; 18:851–855.PubMedCrossRefGoogle Scholar
  4. 4.
    Okuyama R, LeFort K, Dotto GP. A dynamic model of keratinocyte stem cell renewal and differentiation: role of the p21WAF1/Cip1 and Notch1 signaling pathways. J Investig Dermatol Symp Proc 2004; 9:248–252.PubMedCrossRefGoogle Scholar
  5. 5.
    Roninson IB. Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts. Cancer Lett 2002; 179:1–14.PubMedCrossRefGoogle Scholar
  6. 6.
    Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13:1501–1512.PubMedCrossRefGoogle Scholar
  7. 7.
    Gartel AL, Tyner AL. Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res 1999; 246:280–289.PubMedCrossRefGoogle Scholar
  8. 8.
    Jones JM, Cui XS, Medina D, Donehower LA. Heterozygosity of p21WAF1/CIP1 enhances tumor cell proliferation and cyclin D1-associated kinase activity in a murine mammary cancer model. Cell Growth Differ 1999; 10:213–222.PubMedGoogle Scholar
  9. 9.
    Martin-Caballero J, Flores JM, Garcia-Palencia P, Serrano M. Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. Cancer Res 2001; 61:6234–6238.PubMedGoogle Scholar
  10. 10.
    Cayrol C, Ducommun B. Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21. Oncogene 1998; 17:2437–2444.PubMedCrossRefGoogle Scholar
  11. 11.
    Sheaff RJ, Singer JD, Swanger J et al. Proteasomal turnover of p21Cip1 does not require p21Cip1 ubiquitination. Mol Cell 2000; 5:403–410.PubMedCrossRefGoogle Scholar
  12. 12.
    Kriwacki RW, Hengst L, Tennant L et al. Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. Proc Natl Acad Sci U S A 1996; 93:11504–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Verma R, Deshaies RJ. A proteasome howdunit: the case of the missing signal. Cell 2000; 101:341–344.PubMedCrossRefGoogle Scholar
  14. 14.
    Bloom J, Amador V, Bartolini F et al. Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation. Cell 2003; 115:71–82.PubMedCrossRefGoogle Scholar
  15. 15.
    Li Y, Jenkins CW, Nichols MA, Xiong Y. Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. Oncogene 1994; 9:2261–2268.PubMedGoogle Scholar
  16. 16.
    Zhang H, Xiong Y, Beach D. Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes. Mol Biol Cell 1993; 4:897–906.PubMedGoogle Scholar
  17. 17.
    Dotto GP. p21(WAF1/Cip1): more than a break to the cell cycle? Biochim Biophys Acta 2000; 1471:M43–M56.PubMedGoogle Scholar
  18. 18.
    Esteve V, Canela N, Rodriguez-Vilarrupla A et al. The structural plasticity of the C terminus of p21Cip1 is a determinant for target protein recognition. Chembiochem 2003; 4:863–869.PubMedCrossRefGoogle Scholar
  19. 19.
    Maga G, Hubscher U. Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci 2003; 116:3051–3060.PubMedCrossRefGoogle Scholar
  20. 20.
    Gulbis JM, Kelman Z, Hurwitz J et al. Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA. Cell 1996; 87:297–306.PubMedCrossRefGoogle Scholar
  21. 21.
    Touitou RJ, Richardson S, Bose M et al. A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome. EMBO J 2001; 20:2367–2375.PubMedCrossRefGoogle Scholar
  22. 22.
    Bose S, Stratford FL, Broadfoot KI et al. Phosphorylation of 20S proteasome alpha subunit C8 (alpha7) stabilizes the 26S proteasome and plays a role in the regulation of proteasome complexes by gamma-interferon. Biochem J 2004; 378:177–184.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen J, Saha P, Kornbluth S et al. Cyclin-binding motifs are essential for the function of p21CIP1. Mol Cell Biol 1996; 16:4673–4682.PubMedGoogle Scholar
  24. 24.
    Coleman ML, Marshall CJ, Olson MF. Ras promotes p21(Waf1/Cip1) protein stability via a cyclin D1-imposed block in proteasome-mediated degradation. EMBO J 2003; 22:2036–2046.PubMedCrossRefGoogle Scholar
  25. 25.
    Coleman ML, Densham RM, Croft DR, Olson MF. Stability of p21Waf1/Cip1 CDK inhibitor protein is responsive to RhoA-mediated regulation of the actin cytoskeleton. Oncogene 2006; 25:2708–2716.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhu H, Nie L, Maki CG. Cdk2-dependent inhibition of p21 stability via a C-terminal cyclin-binding motif. J Biol Chem 2005; 280:29282–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang Z, Wang H, Li M et al. MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. J Biol Chem 2004; 279:16000–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Brooks CL, Gu W. p53 ubiquitination: Mdm2 and beyond. Mol Cell 2006; 21:307–315.PubMedCrossRefGoogle Scholar
  29. 29.
    Bake RD, Howl J, Nicholl ID. A sychnological cell penetrating peptide mimic of p21(WAF1/CIP1) is pro-apoptogenic. Peptides 2007; 28:731–740.CrossRefGoogle Scholar
  30. 30.
    Ball KL, Lain S, Fahraeus R et al. Cell-cycle arrest and inhibition of Cdk4 activity by small peptides based on the carboxy-terminal domain of p21WAF1. Curr Biol 1997; 7:71–80.PubMedCrossRefGoogle Scholar
  31. 31.
    Kontopidis G, Andrews MJ, McInnes C et al. Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange. Structure 2003; 11:1537–1546.PubMedCrossRefGoogle Scholar
  32. 32.
    Zheleva DI, McInnes C, Gavine AL et al. Highly potent p21(WAF1)-derived peptide inhibitors of CDK-mediated pRb phosphorylation: delineation and structural insight into their interactions with cyclin A. J Pept Res 2002; 60:257–270.PubMedCrossRefGoogle Scholar
  33. 33.
    Warbrick E, Lane DP, Glover DM, Cox LS. A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen. Curr Biol 1995; 5:275–282.PubMedCrossRefGoogle Scholar
  34. 34.
    Jascur T, Brickner H, Salles-Passador I et al. Regulation of p21(WAF1/CIP1) stability by WISp39, a Hsp90 binding TPR protein. Mol Cell 2005; 17:237–249.PubMedCrossRefGoogle Scholar
  35. 35.
    Kurz EU, Lees-Miller SP. DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair (Amst) 2004; 3:889–900.CrossRefGoogle Scholar
  36. 36.
    Rossig L, Jadidi AS, Urbich C et al. Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells. Mol Cell Biol 2001; 21:5644–5657.PubMedCrossRefGoogle Scholar
  37. 37.
    Scott MT, Morrice N, Ball KL. Reversible phosphorylation at the C-terminal regulatory domain of p21(Waf1/Cip1) modulates proliferating cell nuclear antigen binding. J Biol Chem 2000; 275:11529–37.PubMedCrossRefGoogle Scholar
  38. 38.
    Child ES, Mann DJ. The intricacies of p21 phosphorylation: protein/protein interactions, subcellular localization and stability. Cell Cycle 2006; 5:1313–1319.PubMedCrossRefGoogle Scholar
  39. 39.
    Fraser JA, Hupp TR. Chemical genetics approach to identify peptide ligands that selectively stimulate DAPK-1 kinase activity. Biochemistry 2007; 46:2655–2673.PubMedCrossRefGoogle Scholar
  40. 40.
    Scott MT, Ingram A, Ball KL. PDK1-dependent activation of atypical PKC leads to degradation of the p21 tumour modifier protein. EMBO J 2002; 21:6771–6780.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhou BP, Liao Y, Xia W et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 2001; 3:973–982.PubMedCrossRefGoogle Scholar
  42. 42.
    Li Y, Dowbenko D, Lasky LA. AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J Biol Chem 2002; 277:11352–61.PubMedCrossRefGoogle Scholar
  43. 43.
    Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2003; 2:339–345.PubMedCrossRefGoogle Scholar
  44. 44.
    Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998; 12:3499–3511.PubMedCrossRefGoogle Scholar
  45. 45.
    Rossig L, Badorff C, Holzmann Y et al. Glycogen synthase kinase-3 couples AKT-dependent signaling to the regulation of p21Cip1 degradation. J Biol Chem 2002; 277:9684–9689.PubMedCrossRefGoogle Scholar
  46. 46.
    Chen X, Barton LF, Chi Y et al. Ubiquitin-independent degradation of cell-cycle inhibitors by the REGgamma proteasome. Mol Cell 2007; 26:843–852.PubMedCrossRefGoogle Scholar
  47. 47.
    Liu CW, Corboy MJ, DeMartino GN, Thomas PJ. Endoproteolytic activity of the proteasome. Science 2003; 299:408–411.PubMedCrossRefGoogle Scholar
  48. 48.
    Maki CG, Howley PM. Ubiquitination of p53 and p21 is differentially affected by ionizing and UV radiation. Mol Cell Biol 1997; 17:355–363.PubMedGoogle Scholar
  49. 49.
    Chen XY, Chi A, Bloecher R et al. N-acetylation and ubiquitin-independent proteasomal degradation of p21(Cip1). Mol Cell 2004; 16:839–847.PubMedCrossRefGoogle Scholar
  50. 50.
    Rivett AJ, Bose S, Brooks P, Broadfoot KI. Regulation of proteasome complexes by gamma-interferon and phosphorylation. Biochimie 2001; 83:363–366.PubMedCrossRefGoogle Scholar
  51. 51.
    Li X, Amazit L, Long W et al. Ubiquitin-and ATP-independent proteolytic turnover of p21 by the REGgamma-proteasome pathway. Mol Cell 2007; 26:831–842.PubMedCrossRefGoogle Scholar
  52. 52.
    Bendjennat M, Boulaire J, Jascur T et al. UV irradiation triggers ubiquitin-dependent degradation of p21(WAF1) to promote DNA repair. Cell 2003; 114:599–610.PubMedCrossRefGoogle Scholar
  53. 53.
    Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1999; 1:193–199.PubMedCrossRefGoogle Scholar
  54. 54.
    Bornstein G, Bloom J, Sitry-Shevah D et al. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem 2003; 278:25752–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Yu ZK, Gervais JL, Zhang H. Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins. Proc Natl Acad Sci U S A 1998; 95:11324–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang W, Nacusi L, Sheaff RJ, Liu X. Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection. Biochemistry 2005; 44:14553–64.PubMedCrossRefGoogle Scholar
  57. 57.
    Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J 1997; 16:5334–5344.PubMedCrossRefGoogle Scholar
  58. 58.
    Abbas T, Sivaprasad U, Terai K et al. PCNA dependent regulation of p21 ubiquitulation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev 2008; 22:2496–2506.PubMedCrossRefGoogle Scholar
  59. 59.
    Amador V, Ge S, Santamaria PG et al. APC/C(Cdc20) controls the ubiquitin-mediated degradation of p21 in prometaphase. Mol Cell 2007; 27:462–473.PubMedCrossRefGoogle Scholar
  60. 60.
    Lee H, Zeng SX, Lu H. UV Induces p21 rapid turnover independently of ubiquitin and Skp2. J Biol Chem 2006; 281:26876–83.PubMedCrossRefGoogle Scholar
  61. 61.
    Lee JY, Yu SJ, Park YG et al. Glycogen synthase kinase 3beta phosphorylates p21WAF1/CIP1 for proteasomal degradation after UV irradiation. Mol Cell Biol 2007; 27:3187–3198.PubMedCrossRefGoogle Scholar
  62. 62.
    Martinez LA, Yang J, Vazquez ES et al. p21 modulates threshold of apoptosis induced by DNA-damage and growth facto withdrawal in preostrate cancer cells. Carcinogenesis 2002; 23:1289–1296.PubMedCrossRefGoogle Scholar
  63. 63.
    Lee EW, Lee MS, Camus S et al. Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis. EMBO J 2009; 28: 2100–2113.PubMedCrossRefGoogle Scholar
  64. 64.
    Bossis G, Ferrara P, Acquaviva C et al. c-Fos proto-oncoprotein is degraded by the proteasome independently of its own ubiquitinylation in vivo. Mol Cell Biol 2003; 23:7425–7436.PubMedCrossRefGoogle Scholar
  65. 65.
    Kahana C, Asher G, Shaul Y. Mechanisms of protein degradation: an odyssey with ODC. Cell Cycle 2005; 4:1461–1464.PubMedCrossRefGoogle Scholar
  66. 66.
    Asher G, Shaul Y. p53 proteasomal degradation: poly-ubiquitination is not the whole story. Cell Cycle 2005; 4:1015–1018.PubMedCrossRefGoogle Scholar
  67. 67.
    Asher G, Tsvetkov P, Kahana C, Shaul Y. A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Genes Dev 2005; 19:316–321.PubMedCrossRefGoogle Scholar
  68. 68.
    Asher G, Reuven N, Shaul Y. 20S proteasomes and protein degradation “by default”. Bioessays 2006; 28:844–849.PubMedCrossRefGoogle Scholar
  69. 69.
    Sun L, Chen ZJ. The novel functions of ubiquitination in signaling. Curr Opin Cell Biol 2004; 16:119–126.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jennifer A. Fraser
    • 1
  1. 1.Cell Signalling Unit, Edinburgh Cancer Research CentreUniversity of EdinburghEdinburghUK

Personalised recommendations