Hostname: page-component-5cf477f64f-2wr7h Total loading time: 0 Render date: 2025-04-03T18:11:24.493Z Has data issue: false hasContentIssue false
  • English
  • Français

p21 and p27: roles in carcinogenesis and drug resistance

Published online by Cambridge University Press:  01 July 2008

Abde M. Abukhdeir  and
Ben Ho Park
Abde M. Abukhdeir
Affiliation:
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Breast Cancer Research Program, Baltimore, MD, USA.
Ben Ho Park*
Affiliation:
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Breast Cancer Research Program, Baltimore, MD, USA.
*
*Corresponding author: Ben Ho Park, 1650 Orleans Street, CRBI, Room 1M42, Baltimore, MD 21231, USA. Tel: +1 410 502 7399; Fax: +1 410 614 8397; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Human cancers arise from an imbalance of cell growth and cell death. Key proteins that govern this balance are those that mediate the cell cycle. Several different molecular effectors have been identified that tightly regulate specific phases of the cell cycle, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors. Notably, loss of expression or function of two G1-checkpoint CDK inhibitors – p21 (CDKN1A) and p27 (CDKN1B) – has been implicated in the genesis or progression of many human malignancies. Additionally, there is a growing body of evidence suggesting that functional loss of p21 or p27 can mediate a drug-resistance phenotype. However, reports in the literature have also suggested p21 and p27 can promote tumours, indicating a paradoxical effect. Here, we review historic and recent studies of these two CDK inhibitors, including their identification, function, importance to carcinogenesis and finally their roles in drug resistance.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e19
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Evans, T. et al. (1983) Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33, 389-396Google Scholar
2Slingerland, J. and Pagano, M. (2000) Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol 183, 10-17Google Scholar
3Sherr, C.J. (1994) G1 phase progression: cycling on cue. Cell 79, 551-555Google Scholar
4Lew, D.J., Dulic, V. and Reed, S.I. (1991) Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast. Cell 66, 1197-1206Google Scholar
5Xiong, Y. et al. (1991) Human D-type cyclin. Cell 65, 691-699Google Scholar
6Motokura, T. et al. (1991) A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350, 512-515Google Scholar
7Nurse, P. and Thuriaux, P. (1980) Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. Genetics 96, 627-637Google Scholar
8Nurse, P. (1975) Genetic control of cell size at cell division in yeast. Nature 256, 547-551Google Scholar
9Malumbres, M. and Barbacid, M. (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30, 630-641Google Scholar
10Doree, M., Peaucellier, G. and Picard, A. (1983) Activity of the maturation-promoting factor and the extent of protein phosphorylation oscillate simultaneously during meiotic maturation of starfish oocytes. Dev Biol 99, 489-501Google Scholar
11Maller, J., Wu, M. and Gerhart, J.C. (1977) Changes in protein phosphorylation accompanying maturation of Xenopus laevis oocytes. Dev Biol 58, 295-312Google Scholar
12Gautier, J. et al. (1988) Purified maturation-promoting factor contains the product of a Xenopus homolog of the fission yeast cell cycle control gene cdc2+. Cell 54, 433-439Google Scholar
13Dunphy, W.G. et al. (1988) The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis. Cell 54, 423-431Google Scholar
14Norbury, C. and Nurse, P. (1992) Animal cell cycles and their control. Annu Rev Biochem 61, 441-470Google Scholar
15Sherr, C.J. (1993) Mammalian G1 cyclins. Cell 73, 1059-1065Google Scholar
16Lee, M.G. and Nurse, P. (1987) Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 327, 31-35Google Scholar
17Gould, K.L. et al. (1991) Phosphorylation at Thr167 is required for Schizosaccharomyces pombe p34cdc2 function. EMBO J 10, 3297-3309Google Scholar
18Gould, K.L. and Nurse, P. (1989) Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342, 39-45Google Scholar
19Alkarain, A., Jordan, R. and Slingerland, J. (2004) p27 deregulation in breast cancer: prognostic significance and implications for therapy. J Mammary Gland Biol Neoplasia 9, 67-80Google Scholar
20Koff, A. et al. (1991) Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell 66, 1217-1228Google Scholar
21Matsushime, H. et al. (1991) Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65, 701-713Google Scholar
22Meyerson, M. and Harlow, E. (1994) Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol 14, 2077-2086Google Scholar
23Bates, S. et al. (1994) CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1. Oncogene 9, 71-79Google Scholar
24Matsushime, H. et al. (1992) Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71, 323-334Google Scholar
25Dulic, V., Lees, E. and Reed, S.I. (1992) Association of human cyclin E with a periodic G1-S phase protein kinase. Science 257, 1958-1961Google Scholar
26Koff, A. et al. (1992) Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science 257, 1689-1694Google Scholar
27Sherr, C.J. and Roberts, J.M. (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13, 1501-1512Google Scholar
28Kato, J.Y. et al. (1994) Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase. Mol Cell Biol 14, 2713-2721Google Scholar
29Matsuoka, M. et al. (1994) Activation of cyclin-dependent kinase 4 (cdk4) by mouse MO15-associated kinase. Mol Cell Biol 14, 7265-7275Google Scholar
30Malumbres, M. and Barbacid, M. (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1, 222-231Google Scholar
31Fisk, H.A. and Winey, M. (2001) The mouse Mps1p-like kinase regulates centrosome duplication. Cell 106, 95-104Google Scholar
32Okuda, M. et al. (2000) Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103, 127-140Google Scholar
33Meraldi, P. et al. (1999) Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nat Cell Biol 1, 88-93Google Scholar
34Lacey, K.R., Jackson, P.K. and Stearns, T. (1999) Cyclin-dependent kinase control of centrosome duplication. Proc Natl Acad Sci U S A 96, 2817-2822Google Scholar
35Ewen, M.E. (2000) Where the cell cycle and histones meet. Genes Dev 14, 2265-2270Google Scholar
36Hannon, G.J. and Beach, D. (1994) p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371, 257-261Google Scholar
37Serrano, M., Hannon, G.J. and Beach, D. (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704-707Google Scholar
38Guan, K.L. et al. (1994) Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev 8, 2939-2952Google Scholar
39Hirai, H. et al. (1995) Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 15, 2672-2681Google Scholar
40Chan, F.K. et al. (1995) Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol Cell Biol 15, 2682-2688Google Scholar
41Harper, J.W. et al. (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805-816Google Scholar
42el-Deiry, W.S. et al. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817-825Google Scholar
43Polyak, K. et al. (1994) Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59-66Google Scholar
44Toyoshima, H. and Hunter, T. (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67-74Google Scholar
45Matsuoka, S. et al. (1995) p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev 9, 650-662Google Scholar
46Lee, M.H., Reynisdottir, I. and Massague, J. (1995) Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 9, 639-649Google Scholar
47Xiong, Y., Zhang, H. and Beach, D. (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71, 505-514Google Scholar
48Yu, Z.K., Gervais, J.L. and Zhang, H. (1998) 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 95, 11324-11329Google Scholar
49Withers, D.A. et al. (1991) Characterization of a candidate bcl-1 gene. Mol Cell Biol 11, 4846-4853Google Scholar
50Xiong, Y. et al. (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366, 701-704Google Scholar
51Gu, Y., Turck, C.W. and Morgan, D.O. (1993) Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 366, 707-710Google Scholar
52Noda, A. et al. (1994) Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211, 90-98Google Scholar
53Dulic, V. et al. (1994) p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76, 1013-1023Google Scholar
54Koff, A. et al. (1993) Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science 260, 536-539Google Scholar
55Polyak, K. et al. (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8, 9-22Google Scholar
56Zhou, B.P. et al. (2001) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3, 245-252Google Scholar
57Goubin, F. and Ducommun, B. (1995) Identification of binding domains on the p21Cip1 cyclin-dependent kinase inhibitor. Oncogene 10, 2281-2287Google Scholar
58Connor, M.K. et al. (2003) CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis. Mol Biol Cell 14, 201-213Google Scholar
59Cheng, M. et al. (1999) The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 18, 1571-1583Google Scholar
60LaBaer, J. et al. (1997) New functional activities for the p21 family of CDK inhibitors. Genes Dev 11, 847-862Google Scholar
61Planas-Silva, M.D. and Weinberg, R.A. (1997) Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Mol Cell Biol 17, 4059-4069Google Scholar
62Ciarallo, S. et al. (2002) Altered p27(Kip1) phosphorylation, localization, and function in human epithelial cells resistant to transforming growth factor beta-mediated G(1) arrest. Mol Cell Biol 22, 2993-3002Google Scholar
63James, M.K. et al. (2008) Differential modification of p27Kip1 controls its cyclin D-cdk4 inhibitory activity. Mol Cell Biol 28, 498-510Google Scholar
64Westfall, M.D. et al. (2003) The Delta Np63 alpha phosphoprotein binds the p21 and 14-3-3 sigma promoters in vivo and has transcriptional repressor activity that is reduced by Hay-Wells syndrome-derived mutations. Mol Cell Biol 23, 2264-2276Google Scholar
65Coller, H.A. et al. (2000) Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Acad Sci U S A 97, 3260-3265Google Scholar
66Westbrook, T.F. et al. (2002) E7 abolishes raf-induced arrest via mislocalization of p21(Cip1). Mol Cell Biol 22, 7041-7052Google Scholar
67Prabhu, S. et al. (1997) Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol Cell Biol 17, 5888-5896Google Scholar
68MacLachlan, T.K., Takimoto, R. and El-Deiry, W.S. (2002) BRCA1 directs a selective p53-dependent transcriptional response towards growth arrest and DNA repair targets. Mol Cell Biol 22, 4280-4292Google Scholar
69Zheng, L. et al. (2000) Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol Cell 6, 757-768CrossRefGoogle Scholar
70Ouchi, T. et al. (2000) Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. Proc Natl Acad Sci U S A 97, 5208-5213Google Scholar
71Somasundaram, K. et al. (1997) Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature 389, 187-190Google Scholar
72Williamson, E.A., Dadmanesh, F. and Koeffler, H.P. (2002) BRCA1 transactivates the cyclin-dependent kinase inhibitor p27(Kip1). Oncogene 21, 3199-3206Google Scholar
73Timmerbeul, I. et al. (2006) Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. Proc Natl Acad Sci U S A 103, 14009-14014Google Scholar
74Hengst, L. and Reed, S.I. (1996) Translational control of p27Kip1 accumulation during the cell cycle. Science 271, 1861-1864Google Scholar
75Millard, S.S. et al. (1997) Enhanced ribosomal association of p27(Kip1) mRNA is a mechanism contributing to accumulation during growth arrest. J Biol Chem 272, 7093-7098Google Scholar
76Pagano, M. et al. (1995) Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269, 682-685Google Scholar
77Malek, N.P. et al. (2001) A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413, 323-327Google Scholar
78Boehm, M. et al. (2002) A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression. EMBO J 21, 3390-3401Google Scholar
79Sabile, A. et al. (2006) Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein. Mol Cell Biol 26, 5994-6004Google Scholar
80Grimmler, M. et al. (2007) Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell 128, 269-280Google Scholar
81Rodier, G. et al. (2001) p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. Embo J 20, 6672-6682Google Scholar
82Viglietto, G. et al. (2002) Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8, 1136-1144Google Scholar
83Chu, I. et al. (2007) p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell 128, 281-294Google Scholar
84Perez-Roger, I. et al. (1999) Cyclins D1 and D2 mediate myc-induced proliferation via sequestration of p27(Kip1) and p21(Cip1). EMBO J 18, 5310-5320Google Scholar
85Sherr, C.J. and Roberts, J.M. (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9, 1149-1163Google Scholar
86Moeller, S.J., Head, E.D. and Sheaff, R.J. (2003) p27Kip1 inhibition of GRB2-SOS formation can regulate Ras activation. Mol Cell Biol 23, 3735-3752Google Scholar
87McAllister, S.S. et al. (2003) Novel p27(kip1) C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions. Mol Cell Biol 23, 216-228Google Scholar
88Besson, A. et al. (2004) p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev 18, 862-876Google Scholar
89Allan, L.A. et al. (2000) The p21(WAF1/CIP1) promoter is methylated in Rat-1 cells: stable restoration of p53-dependent p21(WAF1/CIP1) expression after transfection of a genomic clone containing the p21(WAF1/CIP1) gene. Mol Cell Biol 20, 1291-1298Google Scholar
90Roman-Gomez, J. et al. (2002) 5’ CpG island hypermethylation is associated with transcriptional silencing of the p21(CIP1/WAF1/SDI1) gene and confers poor prognosis in acute lymphoblastic leukemia. Blood 99, 2291-2296Google Scholar
91Balbin, M. et al. (1996) Functional analysis of a p21WAF1,CIP1,SDI1 mutant (Arg94 –> Trp) identified in a human breast carcinoma. Evidence that the mutation impairs the ability of p21 to inhibit cyclin-dependent kinases. J Biol Chem 271, 15782-15786Google Scholar
92Brugarolas, J. et al. (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377, 552-557Google Scholar
93Deng, C. et al. (1995) Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675-684Google Scholar
94Topley, G.I. et al. (1999) p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. Proc Natl Acad Sci U S A 96, 9089-9094Google Scholar
95Poole, A.J. et al. (2004) Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon. Oncogene 23, 8128-8134Google Scholar
96Jackson, R.J. et al. (2003) p21Cip1 nullizygosity increases tumor metastasis in irradiated mice. Cancer Res 63, 3021-3025Google Scholar
97Yang, W. et al. (2005) Inactivation of p21WAF1/cip1 enhances intestinal tumor formation in Muc2−/− mice. Am J Pathol 166, 1239-1246Google Scholar
98Yang, W.C. et al. (2001) Targeted inactivation of the p21(WAF1/cip1) gene enhances Apc-initiated tumor formation and the tumor-promoting activity of a Western-style high-risk diet by altering cell maturation in the intestinal mucosal. Cancer Res 61, 565-569Google Scholar
99Martin-Caballero, J. et al. (2001) Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. Cancer Res 61, 6234-6238Google Scholar
100Fero, M.L. et al. (1998) The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396, 177-180Google Scholar
101Kiyokawa, H. et al. (1996) Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85, 721-732Google Scholar
102Nakayama, K. et al. (1996) Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707-720Google Scholar
103Philipp-Staheli, J. et al. (2004) Distinct roles for p53, p27Kip1, and p21Cip1 during tumor development. Oncogene 23, 905-913Google Scholar
104Di Cristofano, A. et al. (2001) Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 27, 222-224Google Scholar
105Park, M.S. et al. (1999) p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice. Proc Natl Acad Sci U S A 96, 6382-6387Google Scholar
106Martin-Caballero, J. et al. (2004) Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice. Oncogene 23, 8231-8237Google Scholar
107Philipp-Staheli, J. et al. (2002) Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice. Cancer Cell 1, 355-368Google Scholar
108De la Cueva, E. et al. (2006) Tumorigenic activity of p21Waf1/Cip1 in thymic lymphoma. Oncogene 25, 4128-4132CrossRefGoogle Scholar
109Wang, Y.A., Elson, A. and Leder, P. (1997) Loss of p21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm-deficient mice. Proc Natl Acad Sci U S A 94, 14590-14595Google Scholar
110Liu, Y. et al. (2007) Somatic cell type specific gene transfer reveals a tumor-promoting function for p21(Waf1/Cip1). EMBO J 26, 4683-4693Google Scholar
111Besson, A. et al. (2007) Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev 21, 1731-1746Google Scholar
112Pellegata, N.S. et al. (2006) Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A 103, 15558-15563Google Scholar
113Hotta, K. et al. (2007) Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation. Oncol Rep 17, 313-317Google Scholar
114Tsai, M.F. et al. (2006) A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst 98, 825-838Google Scholar
115Delahunt, B., Bethwaite, P.B. and Nacey, J.N. (2007) Outcome prediction for renal cell carcinoma: evaluation of prognostic factors for tumours divided according to histological subtype. Pathology 39, 459-465Google Scholar
116Puhalla, H. et al. (2007) Expression of p21(Wafl/Cip1), p57(Kip2) and HER2/neu in patients with gallbladder cancer. Anticancer Res 27, 1679-1684Google Scholar
117Mizokami, K. et al. (2006) Relationship of hypoxia-inducible factor 1alpha and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer. World J Surg Oncol 4, 94Google Scholar
118Villwock Mde, M. et al. (2006) Prevalence of p21 immunohistochemical expression in esophageal adenocarcinoma. Arq Gastroenterol 43, 212-218Google Scholar
119Pijnenborg, J.M. et al. (2006) TP53 overexpression in recurrent endometrial carcinoma. Gynecol Oncol 100, 397-404Google Scholar
120Li, G. et al. (2005) Genetic polymorphisms of p21 are associated with risk of squamous cell carcinoma of the head and neck. Carcinogenesis 26, 1596-1602Google Scholar
121Bali, A. et al. (2004) Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer. Clin Cancer Res 10, 5168-5177Google Scholar
122Anttila, M.A. et al. (1999) p21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer. Br J Cancer 79, 1870-1878Google Scholar
123Viale, G. et al. (1999) p21WAF1/CIP1 expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations. J Pathol 187, 302-307Google Scholar
124Caffo, O. et al. (1996) Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up. Clin Cancer Res 2, 1591-1599Google Scholar
125Bukholm, I.K. et al. (1997) Relationship between abnormal p53 protein and failure to express p21 protein in human breast carcinomas. J Pathol 181, 140-145Google Scholar
126Domagala, W. et al. (2001) p21/WAF1/Cip1 expression in invasive ductal breast carcinoma: relationship to p53, proliferation rate, and survival at 5 years. Virchows Arch 439, 132-140Google Scholar
127Hemmati, P.G. et al. (2005) Loss of p21 disrupts p14 ARF-induced G1 cell cycle arrest but augments p14 ARF-induced apoptosis in human carcinoma cells. Oncogene 24, 4114-4128Google Scholar
128McBride, S.R., Leonard, N. and Reynolds, N.J. (2002) Loss of p21(WAF1) compartmentalisation in sebaceous carcinoma compared with sebaceous hyperplasia and sebaceous adenoma. J Clin Pathol 55, 763-766Google Scholar
129Porter, P.L. et al. (1997) Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 3, 222-225Google Scholar
130Xia, W. et al. (2004) 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 10, 3815-3824Google Scholar
131Bachman, K.E. et al. (2004) 21(WAF1/CIP1) mediates the growth response to TGF-beta in human epithelial cells. Cancer Biol Ther 3, 221-225Google Scholar
132Blain, S.W. and Massague, J. (2002) Breast cancer banishes p27 from nucleus. Nat Med 8, 1076-1078Google Scholar
133Liang, J. et al. (2002) PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8, 1153-1160Google Scholar
134Shin, I. et al. (2002) PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 8, 1145-1152Google Scholar
135Silva, J. et al. (2007) Akt-Induced Tamoxifen Resistance is Associated with Altered FKHR Regulation. Cancer Invest 1-5Google Scholar
136deGraffenried, L.A. et al. (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 10, 8059-8067Google Scholar
137Campbell, R.A. et al. (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276, 9817-9824Google Scholar
138Cariou, S. et al. (2000) Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. Proc Natl Acad Sci U S A 97, 9042-9046Google Scholar
139Giannakakou, P. et al. (2001) Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity. Oncogene 20, 3806-3813Google Scholar
140Schmidt, M. and Fan, Z. (2001) Protection against chemotherapy-induced cytotoxicity by cyclin-dependent kinase inhibitors (CKI) in CKI-responsive cells compared with CKI-unresponsive cells. Oncogene 20, 6164-6171Google Scholar
141Shang, Y. and Brown, M. (2002) Molecular determinants for the tissue specificity of SERMs. Science 295, 2465-2468Google Scholar
142Anonymous, (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 351, 1451-1467Google Scholar
143Canney, P.A. et al. (1987) Clinical significance of tamoxifen withdrawal response. Lancet 1, 36Google Scholar
144Michalides, R. et al. (2004) Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer. Cancer Cell 5, 597-605Google Scholar
145Rayala, S.K., Molli, P.R. and Kumar, R. (2006) Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity. Cancer Res 66, 5985-5988Google Scholar
146Shou, J. et al. (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96, 926-935Google Scholar
147Abukhdeir, A.M. et al. (2008) Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proc Natl Acad Sci U S A 105, 288-293Google Scholar
148Jankevicius, F. et al. (2002) p21 and p53 Immunostaining and survival following systemic chemotherapy for urothelial cancer. Urol Int 69, 174-180Google Scholar
149Kuwahara, M. et al. (1999) p53, p21(Waf1/Cip1) and cyclin D1 protein expression and prognosis in esophageal cancer. Dis Esophagus 12, 116-119Google Scholar
150Cheng, J.D. et al. (1999) Paradoxical correlations of cyclin-dependent kinase inhibitors p21waf1/cip1 and p27kip1 in metastatic colorectal carcinoma. Clin Cancer Res 5, 1057-1062Google Scholar

Further reading, resources and contacts

The Reactome website is a curated knowledge base of biological pathways where readers can learn more about the cell cycle and other pathways:

Branzei, D. and Foiani, M. (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9, 297-308Google Scholar
Park, B.H. and Vogelstein, B. (2005) Tumor suppressor genes. In Cancer Medicine 7 (Kufe, D. et al. , eds), BC Decker, Hamilton Ontario, pp. 85-103Google Scholar
http://www.genomeknowledge.org/cgi-bin/frontpage?DB=gk_currentGoogle Scholar
http://www.sanger.ac.uk/genetics/CGP/cosmic/Google Scholar
Branzei, D. and Foiani, M. (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9, 297-308Google Scholar
Park, B.H. and Vogelstein, B. (2005) Tumor suppressor genes. In Cancer Medicine 7 (Kufe, D. et al. , eds), BC Decker, Hamilton Ontario, pp. 85-103Google Scholar
http://www.genomeknowledge.org/cgi-bin/frontpage?DB=gk_currentGoogle Scholar
http://www.sanger.ac.uk/genetics/CGP/cosmic/Google Scholar