Examination of the Expanding Pathways for the Regulation of P21 Expression and Activity

Overview

Journal Cell Signal

Date 2010 Jan 27

PMID 20100570

Citations 213

Authors

Yong-Sam Jung

Yingjuan Qian

Xinbin Chen

Affiliations

Soon will be listed here.

Abstract

p21(Waf1/Cip1/Sdi1) was originally identified as an inhibitor of cyclin-dependent kinases, a mediator of p53 in growth suppression and a marker of cellular senescence. p21 is required for proper cell cycle progression and plays a role in cell death, DNA repair, senescence and aging, and induced pluripotent stem cell reprogramming. Although transcriptional regulation is considered to be the initial control point for p21 expression, there is growing evidence that post-transcriptional and post-translational regulations play a critical role in p21 expression and activity. This review will briefly discuss the activity of p21 and focus on current knowledge of the determinants that control p21 transcription, mRNA stability and translation, and protein stability and activity.

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References

Gerards W, de Jong W, Boelens W, Bloemendal H . Structure and assembly of the 20S proteasome. Cell Mol Life Sci. 1998; 54(3):253-62. PMC: 11147335. DOI: 10.1007/s000180050147. View

Grosshans H, Johnson T, Reinert K, Gerstein M, Slack F . The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans. Dev Cell. 2005; 8(3):321-30. DOI: 10.1016/j.devcel.2004.12.019. View

Chang T, Mendell J . microRNAs in vertebrate physiology and human disease. Annu Rev Genomics Hum Genet. 2007; 8:215-39. DOI: 10.1146/annurev.genom.8.080706.092351. View

Minucci S, Pelicci P . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006; 6(1):38-51. DOI: 10.1038/nrc1779. View

Xiong Y, Zhang H, Beach D . D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell. 1992; 71(3):505-14. DOI: 10.1016/0092-8674(92)90518-h. View

Niculescu 3rd A, Chen X, Smeets M, Hengst L, Prives C, Reed S . Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol. 1998; 18(1):629-43. PMC: 121530. DOI: 10.1128/MCB.18.1.629. View

Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E, Henson J . HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal. Cell. 1991; 67(2):325-33. DOI: 10.1016/0092-8674(91)90184-z. View

Gartel A, Ye X, Goufman E, Shianov P, Hay N, Najmabadi F . Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proc Natl Acad Sci U S A. 2001; 98(8):4510-5. PMC: 31865. DOI: 10.1073/pnas.081074898. View

Okita K, Ichisaka T, Yamanaka S . Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448(7151):313-7. DOI: 10.1038/nature05934. View

10.

Gartel A, Tyner A . Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res. 1999; 246(2):280-9. DOI: 10.1006/excr.1998.4319. View

11.

Zhang J, Chen X, Kent M, Rodriguez C, Chen X . Establishment of a dog model for the p53 family pathway and identification of a novel isoform of p21 cyclin-dependent kinase inhibitor. Mol Cancer Res. 2009; 7(1):67-78. PMC: 2653090. DOI: 10.1158/1541-7786.MCR-08-0347. View

12.

Xia W, Chen J, Zhou X, Sun P, Lee D, Liao Y . Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clin Cancer Res. 2004; 10(11):3815-24. DOI: 10.1158/1078-0432.CCR-03-0527. View

13.

Agrawal S, Agarwal M, Chatterjee-Kishore M, Stark G, Chisolm G . Stat1-dependent, p53-independent expression of p21(waf1) modulates oxysterol-induced apoptosis. Mol Cell Biol. 2002; 22(7):1981-92. PMC: 133680. DOI: 10.1128/MCB.22.7.1981-1992.2002. View

14.

Iakova P, Wang G, Timchenko L, Michalak M, Pereira-Smith O, Smith J . Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate. EMBO J. 2004; 23(2):406-17. PMC: 1271759. DOI: 10.1038/sj.emboj.7600052. View

15.

Al-Mohanna M, Al-Khalaf H, Al-Yousef N, Aboussekhra A . The p16INK4a tumor suppressor controls p21WAF1 induction in response to ultraviolet light. Nucleic Acids Res. 2006; 35(1):223-33. PMC: 1802571. DOI: 10.1093/nar/gkl1075. View

16.

Willis A, Chen X . The promise and obstacle of p53 as a cancer therapeutic agent. Curr Mol Med. 2002; 2(4):329-45. DOI: 10.2174/1566524023362474. View

17.

Wang W, Nacusi L, Sheaff R, Liu X . Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection. Biochemistry. 2005; 44(44):14553-64. DOI: 10.1021/bi051071j. View

18.

Lal A, Mazan-Mamczarz K, Kawai T, Yang X, Martindale J, Gorospe M . Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs. EMBO J. 2004; 23(15):3092-102. PMC: 514922. DOI: 10.1038/sj.emboj.7600305. View

19.

Beckerman R, Donner A, Mattia M, Peart M, Manley J, Espinosa J . A role for Chk1 in blocking transcriptional elongation of p21 RNA during the S-phase checkpoint. Genes Dev. 2009; 23(11):1364-77. PMC: 2701578. DOI: 10.1101/gad.1795709. View

20.

Gartel A, Radhakrishnan S, Serfas M, Kwon Y, Tyner A . A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues. Oncogene. 2004; 23(49):8154-7. DOI: 10.1038/sj.onc.1207820. View