Skip to main content
SpringerLink
Log in
Book cover

Cell Cycle Inhibitors in Cancer Therapy pp 11–29Cite as

p27, A Prognostic Indicator Reflecting ...?

  • Chapter

  • 147 Accesses

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Summary

Over the last five years, the expression of p27kipl, a cyclin-dependent kinase inhibitor, has proved to be a strong prognostic indicator for long-term survival of patients with tumors of the colon, breast, prostate, lung, pituitary, and many other tissues. Tumors arising in these organs that were not expressing p27 protein tended to be more aggressive and patients had a poorer clinical outcome. However, it is not clear why p27 was such a strong prognostic indicator in multiple tissues. Furthermore, before p27 is brought into widespread clinical use, prospective studies will be required to validate, in advance, a clinical course or response to therapy. Without the essential knowledge of what low p27 prognosticates, vis a vis the evolution of the tumor, validation will be difficult. Because there is no possibility of determining directly how low p27 expression facilitates tumor development in humans, we have turned to developing mouse models. However, we had to first ask the following questions: Does p27 deficiency contribute to tumor development in the mouse? If p27 deficiency contributed to tumor development, does it mimic the human condition, i.e., were tumors more aggressive? Then, if they were more aggressive, what was the mechanism underlying this? Before we begin to discuss these issues, I apologize to the many investigators whose work will be either uncited or cited only by review.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med 1999; 50: 401–423.

    Article  PubMed  CAS  Google Scholar 

  2. Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, Scheithauer BW. p27kipl: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 1999; 154: 313–323.

    Article  PubMed  CAS  Google Scholar 

  3. Sgambato A, Cittadini A, Faraglia B, Weinstein IB. Multiple functions of p27(Kipl) and its alterations in tumor cells: a review. J Cell Physiol 2000; 183: 18–27.

    Article  PubMed  CAS  Google Scholar 

  4. Slingerland J, Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol 2000; 183: 10–17.

    Article  PubMed  CAS  Google Scholar 

  5. Barnouin K, Fredersdorf S, Eddaoudi A, Mittnacht S, Pan LX, Du MQ, Lu X. Antiproliferative function of p27kipl is frequently inhibited in highly malignant Burkitt’s lymphoma cells. Oncogene 1999; 18: 6388–6397.

    Article  PubMed  CAS  Google Scholar 

  6. Sanchez-Beato M, Camacho FI, Martinez-Montero JC, Saez AI, Villuendas R, Sanchez-Verde, L, et al. Anomalous high p27/KIP1 expression in a subset of aggressive B-cell lymphomas is associated with cyclin D3 overexpression. p27/KIP1-cyclin D3 colocalization in tumor cells. Blood 1999; 94: 765–772.

    PubMed  CAS  Google Scholar 

  7. Masciullo V, Sgambato A, Pacilio C, Pucci B, Ferrandina G, Palazzo J, et al. Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer. Cancer Res 1999; 59: 3790–3794.

    PubMed  CAS  Google Scholar 

  8. Singh SP, Lipman J, Goldman H, Ellis FH Jr, Aizenman L, Cangi MG, et al. Loss or altered subcellular localization of p27 in Barrett’s associated adenocarcinoma. Cancer Res 1998; 58: 1730–1735.

    PubMed  CAS  Google Scholar 

  9. Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dey 1994; 8: 9–22.

    Article  CAS  Google Scholar 

  10. Soos T J, Kiyokawa H, Yan JS, Rubin MS, Giordano A, DeBlasio A, et al. Formation of p27CDK complexes during the human mitotic cell cycle. Cell Growth Differ 1996; 7: 135–146.

    PubMed  CAS  Google Scholar 

  11. Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, et al. Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J 1999; 18: 5321–5333.

    Article  PubMed  CAS  Google Scholar 

  12. Wang G, Miskimins R, Miskimins WK. The cyclin-dependent kinase inhibitor p27Kipl is localized to the cytosol in Swiss/3T3 cells. Oncogene 1999; 18: 5204–5210.

    Article  PubMed  CAS  Google Scholar 

  13. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kipl is instigated by Jabl. Nature 1999; 398: 160–165.

    Article  PubMed  CAS  Google Scholar 

  14. Smitherman M, Lee K, Swanger J, Kapur R, Clurman BE. Characterization and targeted disruption of murine nup50, a p27(Kip 1)-interacting component of the nuclear pore complex In Process Citation]. Mol Cell Biol 2000; 20: 5631–5642.

    Article  PubMed  CAS  Google Scholar 

  15. Soucek T, Yeung RS, Hengstschlager M. Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2. Proc Natl Acad Sci USA 1998; 95: 15653–15658.

    Article  PubMed  CAS  Google Scholar 

  16. Ponce-Castaneda MV, Lee MH, Latres E, Polyak K, Lacombe L, Montgomery K, et al. p27Kipl: chromosomal mapping to 12p12–12p13.1 and absence of mutations in human tumors. Cancer Res 1995; 55: 1211–1214.

    PubMed  CAS  Google Scholar 

  17. Pietenpol JA, Bohlander SK, Sato Y, Papadopoulos N, Liu B, Friedman C, et al. Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias. Cancer Res 1995; 55: 1206–1210.

    PubMed  CAS  Google Scholar 

  18. Bullrich F, MacLachlan TK, Sang N, Druck T, Veronese ML, Allen SL, et al. Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27Kipl, to regions involved in human cancer. Cancer Res 1995; 55: 1199–1205.

    PubMed  CAS  Google Scholar 

  19. Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ. The murine gene p27Kipl is haploinsufficient for tumour suppression. Nature 1998; 396: 177–180.

    Article  PubMed  CAS  Google Scholar 

  20. Philipp J, Vo K, Gurley KE, Seidel K, Kemp CJ. Tumor suppression by p27Kip 1 and p21 Cip 1 during chemically induced skin carcinogenesis. Oncogene 1999; 18: 4689–4698.

    Article  PubMed  CAS  Google Scholar 

  21. Park MS, Rosai J, Nguyen HT, Capodieci P, Cordon-Cardo C, Koff A. p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice. Proc Natl Acad Sci USA 1999; 96: 6382–6387.

    Article  PubMed  CAS  Google Scholar 

  22. Elledge SJ, Harper JW. The role of protein stability in the cell cycle and cancer. Biochim Biophys Acta 1998; 1377: M61 - M70.

    PubMed  CAS  Google Scholar 

  23. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995; 269: 682–685.

    Article  PubMed  CAS  Google Scholar 

  24. Piva R, Cancelli I, Cavalla P, Bortolotto S, Dominguez J, Draetta GF, Schiffer D. Proteasomedependent degradation of p27/kipl in gliomas. JNeuropathol Exp Neurol 1999; 58: 691–696.

    Article  CAS  Google Scholar 

  25. Agus DB, Cordon-Cardo C, Fox W, Drobnjak M, Koff A, Golde D W, Scher HI. Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence. J Natl Cancer Inst 1999; 91: 1869–1876.

    Article  PubMed  CAS  Google Scholar 

  26. Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, et al. Increased proteasomedependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 1997; 3: 231–234.

    Article  PubMed  CAS  Google Scholar 

  27. Shamma A, Doki Y, Tsujinaka T, Shiozaki H, Inoue M, Yano M, et al. Loss of p27(KIP1) expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Oncology 2000; 58: 152–158.

    Article  PubMed  CAS  Google Scholar 

  28. Cavalla P, Piva R, Bortolotto S, Grosso R, Cancelli I, Chio A, Schiffer D. p27/kipl expression in oligodendrogliomas and its possible prognostic role. Acta Neuropathol (Berl) 1999; 98: 629–634.

    Article  CAS  Google Scholar 

  29. Palmqvist R, Stenling R, Landberg G. Prognostic significance of p27(Kipl) expression in colorectal cancer: a clinico-pathological characterization. J Pathol 1999; 188: 18–23.

    Article  PubMed  CAS  Google Scholar 

  30. Agrawal D, Hauser P, McPherson F, Dong F, Garcia A, Pledger WJ. Repression of p27kip 1 synthesis by platelet-derived growth factor in BALB/c 3T3 cells. Mol Cell Biol 1996; 16: 4327–4336.

    PubMed  CAS  Google Scholar 

  31. Millard SS, Yan JS, Nguyen H, Pagano M, Kiyokawa H, and Koff A. Enhanced ribosomal association of p27(Kip 1) mRNA is a mechanism contributing to accumulation during growth arrest. J Biol Chem 1997; 272: 7093–7098.

    Article  PubMed  CAS  Google Scholar 

  32. Millard SS, Vidal A, Markus M, Koff A. A U-Rich Element in the 5’ untranslated region is necessary for the translation of p27 mRNA. Mol Cell Biol 2000; 20: 5947–5959.

    Article  PubMed  CAS  Google Scholar 

  33. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.

    Article  PubMed  CAS  Google Scholar 

  34. Reed SI. Control of the Gl/S transition. Cancer Sury 1997; 29: 7–23.

    CAS  Google Scholar 

  35. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev 1999; 13: 1181–1189.

    Article  PubMed  CAS  Google Scholar 

  36. Morisaki H, Fujimoto A, Ando A, Nagata Y, Ikeda K, Nakanishi M. Cell cycle-dependent phosphorylation of p27 cyclin-dependent kinase (Cdk) inhibitor by cyclin E/Cdk2. Biochem Biophys Res Commun 1997; 240: 386–390.

    Article  PubMed  CAS  Google Scholar 

  37. Mueller A, Odze R, Jenkins TD, Shahsesfaei A, Nakagawa H, Inomoto T, Rustgi AK. A transgenic mouse model with cyclin D1 overexpression results in cell cycle, epidermal growth factor receptor, and p53 abnormalities. Cancer Res 1997; 57: 5542–5549.

    PubMed  CAS  Google Scholar 

  38. Nguyen H, Gitig DM, Koff A. Cell-free degradation of p27(kipl), a G1 cyclin-dependent kinase inhibitor, is dependent on CDK2 activity and the proteasome. Mol Cell Biol 1999; 19: 1190–1201.

    PubMed  CAS  Google Scholar 

  39. Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE. Cyclin E-CDK2 is a regulator of p27Kipl. Genes Dev 1997; 11: 1464–1478.

    Article  PubMed  CAS  Google Scholar 

  40. Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclindependent kinase inhibitor p27. EMBO J 1997; 16: 5334–5344.

    Article  PubMed  CAS  Google Scholar 

  41. Nigg EA, Blangy A, Lane HA. Dynamic changes in nuclear architecture during mitosis: on the role of protein phosphorylation in spindle assembly and chromosome segregation. Exp Cell Res 1996; 229: 174–180.

    Article  PubMed  CAS  Google Scholar 

  42. Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999; 98: 859–869.

    Article  PubMed  CAS  Google Scholar 

  43. Cheng M, Sexl V, Sherr CJ, Roussel MF. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc Natl Acad Sci USA 1998; 95: 1091–1096.

    Article  PubMed  CAS  Google Scholar 

  44. Roussel MF, Theodoras AM, Pagano M, Sherr CJ. Rescue of defective mitogenic signaling by D-type cyclins. Proc Natl Acad Sci USA 1995; 92: 6837–6841.

    Article  PubMed  CAS  Google Scholar 

  45. Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY. D-type cyclindependent kinase activity in mammalian cells. Mol Cell Biol 1994; 14: 2066–2076.

    PubMed  CAS  Google Scholar 

  46. Reynisdottir I, Polyak K, lavarone A, Massague J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev 1995; 9: 1831–1845.

    Article  PubMed  CAS  Google Scholar 

  47. Kiyokawa H., Koff A. Roles of cyclin-dependent kinase inhibitors: lessons from knock-out mice. Curr Topics Microbiol Immunol 1997; 227: 105–120.

    Article  Google Scholar 

  48. Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ. The p21(Cipl) and p27(Kip1) CDK `inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 1999; 18: 1571–1583.

    Article  PubMed  CAS  Google Scholar 

  49. Zhang H, Hannon GJ, Beach D. p21-containing cyclin kinases exist in both active and inactive states. Genes Dey 1994; 8: 1750–1758.

    Article  CAS  Google Scholar 

  50. Cross FR. Cell cycle arrest caused by CLN gene deficiency in Saccharomyces cerevisiae resembles START-I arrest and is independent of the mating-pheromone signalling pathway. Mol Cell Biol 1990; 10: 6482–6490.

    PubMed  CAS  Google Scholar 

  51. Richardson HE, Wittenberg C, Cross F, Reed SI. An essential GI function for cyclin-like proteins in yeast. Cell 1989; 59: 1127–1133.

    Article  PubMed  CAS  Google Scholar 

  52. Kato JY, Sherr CJ. Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1. Proc Nail Acad Sci USA 1993; 90: 11513–11517.

    Article  CAS  Google Scholar 

  53. Skapek SX, Rhee J, Spicer DB, Lassar AB. Inhibition of myogenic differentiation in proliferating myoblasts by cyclin Dl-dependent kinase. Science 1995; 267: 1022–1024.

    Article  PubMed  CAS  Google Scholar 

  54. Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, et al. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 1995; 267: 1018–1021.

    Article  PubMed  CAS  Google Scholar 

  55. Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP. Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dey 1996; 10: 142–153.

    Article  CAS  Google Scholar 

  56. Tikoo R, Osterhout DJ, Casaccia-Bonnefil P, Seth P, Koff A, Chao MV. Ectopic expression of p27Kip 1 in oligodendrocyte progenitor cells results in cell-cycle growth arrest. JNeurobiol 1998; 36: 431–440.

    Article  CAS  Google Scholar 

  57. Bortner DM, Rosenberg MP. Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 1997; 17: 453–459.

    CAS  Google Scholar 

  58. Bortner DM, Rosenberg MP. Overexpression of cyclin A in the mammary glands of transgenic mice results in the induction of nuclear abnormalities and increased apoptosis. Cell Growth Differ 1995; 6: 1579–1589.

    PubMed  CAS  Google Scholar 

  59. Gomez Lahoz E, Liegeois NJ, Zhang P, Engelman JA, Horner J, Silverman A, et al. Cyclin D- and E-dependent kinases and the p57(KIP2) inhibitor: cooperative interactions in vivo. Mol Cell Biol 1999; 19: 353–363.

    Google Scholar 

  60. Jenkins TD, Mueller A, Odze R, Shahsafaei A, Zukerberg LR, Kent R, et al. Cyclin D1 overexpression combined with N-nitrosomethylbenzylamine increases dysplasia and cellular proliferation in murine esophageal squamous epithelium. Oncogene 1999; 18: 59–66.

    Article  PubMed  CAS  Google Scholar 

  61. Karsunky H, Geisen C, Schmidt T, Haas K, Zevnik B, Gau E, Moroy T. Oncogenic potential of cyclin E in T-cell lymphomagenesis in transgenic mice: evidence for cooperation between cyclin E and Ras but not Myc. Oncogene 1999; 18: 7816–7824.

    CAS  Google Scholar 

  62. Klug DB, Crouch E, Carter C, Coghlan L, Conti CJ, Richie ER. Transgenic expression of cyclin D1 in thymic epithelial precursors promotes epithelial and T cell development. J Immunol 2000; 164: 1881–1888.

    PubMed  CAS  Google Scholar 

  63. Lovec H, Grzeschiczek A, Kowalski MB, Moroy T. Cyclin Dl/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J 1994a; 13: 3487–3495.

    PubMed  CAS  Google Scholar 

  64. Lovec H, Sewing A, Lucibello FC, Muller R, Moroy T. Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras: link between cell cycle control and malignant transformation. Onco gene 1994b; 9: 323–326.

    CAS  Google Scholar 

  65. Ma ZQ, Chua SS, DeMayo FJ, Tsai SY. Induction of mammary gland hyperplasia in transgenic mice over-expressing human Cdc25B. Oncogene 1999; 18: 4564–4576.

    Article  PubMed  CAS  Google Scholar 

  66. Muller D, Bouchard C, Rudolph B, Steiner P, Stuckmann I, Saffrich R, et al. Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes. Oncogene 1997; 15: 2561–2576.

    Article  PubMed  CAS  Google Scholar 

  67. Nakagawa H, Wang TC, Zukerberg L, Odze R, Togawa K, May GH, et al. The targeting of the cyclin D1 oncogene by an Epstein-Barr virus promoter in transgenic mice causes dysplasia in the tongue, esophagus and forestomach. Oncogene 1997; 14: 1185–1190.

    Article  PubMed  CAS  Google Scholar 

  68. Pierce AM, Fisher SM, Conti CJ, Johnson DG. Deregulated expression of E2F1 induces hyperplasia and cooperates with ras in skin tumor development. Oncogene 1998a; 16: 1267–1276.

    Article  PubMed  CAS  Google Scholar 

  69. Pierce AM, Gimenez-Conti IB, Schneider-Broussard R, Martinez LA, Conti CJ, Johnson DG. Increased E2F1 activity induces skin tumors in mice heterozygous and nullizygous for p53. Proc Natl Acad Sci USA 1998b; 95: 8858–8863.

    Article  PubMed  CAS  Google Scholar 

  70. Pierce AM, Schneider-Broussard R, Gimenez-Conti IB, Russell JL, Conti CJ, and Johnson DG. E2F1 has both oncogenic and tumor-suppressive properties in a transgenic model. Mol Cell Biol 1999; 19: 6408–6414.

    PubMed  CAS  Google Scholar 

  71. Robles AI, Larcher F, Whalin RB, Murillas R, Richie E, Gimenez-Conti IB, et al. Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia. Proc Natl Acad Sci USA 1996; 93: 7634–7638.

    Article  PubMed  CAS  Google Scholar 

  72. Rodriguez-Puebla ML, LaCava M, Conti CJ. Cyclin D1 overexpression in mouse epidermis increases cyclin-dependent kinase activity and cell proliferation in vivo but does not affect skin tumor development. Cell Growth Differ 1999; 10: 467–472.

    PubMed  CAS  Google Scholar 

  73. Stepanova L, Finegold M, DeMayo F, Schmidt EV, Harper JW. The oncoprotein kinase chaperone CDC37 functions as an oncogene in mice and collaborates with both c-myc and cyclin D1 in transformation of multiple tissues. Mol Cell Biol 2000; 20: 4462–4473.

    Article  PubMed  CAS  Google Scholar 

  74. Wang D, Russell JL, Johnson DG. E2F4 and E2F1 have similar proliferative properties but different apoptotic and oncogenic properties in vivo. Mol Cell Biol 2000; 20: 3417–3424.

    Article  PubMed  CAS  Google Scholar 

  75. Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV. Mammary hyperplasia and carcinoma in MMTV-cyclin Dl transgenic mice. Nature 1994; 369: 669–671.

    Article  PubMed  CAS  Google Scholar 

  76. Vidal A, Koff A. Cell-cycle inhibitors: three families united by a common cause. Gene 2000; 247: 1–15.

    Article  PubMed  CAS  Google Scholar 

  77. Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 1999; 22: 44–52.

    Article  PubMed  CAS  Google Scholar 

  78. Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kipl) activity. Mol Cell Biol 1999; 19: 7011–7019.

    PubMed  CAS  Google Scholar 

  79. Franklin DS, Godfrey VL, Lee H, Kovalev GI, Schoonhoven R, Chen-Kiang S, et al. CDK inhibitors p18(INK4c) and p27(Kipl) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 1998; 12: 2899–2911.

    Article  PubMed  CAS  Google Scholar 

  80. Resnitzky D, Reed SI. Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Mol Cell Biol 1995; 15: 3463–3469.

    CAS  Google Scholar 

  81. Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li T, et al. Rescue of cyclin Dl deficiency by knockin cyclin E. Cell 1999; 97: 767–777.

    CAS  Google Scholar 

  82. Adachi M, Torigoe T, Takayama S, Imai K. BAG-1 and Bc1–2 in IL-2 signaling. Leuk Lymphoma 1998; 30: 483–491.

    PubMed  CAS  Google Scholar 

  83. Besmer P. The kit ligand encoded at the murine Steel locus: a pleiotropic growth and differentiation factor. Curr Opin Cell Biol 1991; 3: 939–946.

    Article  PubMed  CAS  Google Scholar 

  84. Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 1998a; 10: 262–267.

    Article  PubMed  CAS  Google Scholar 

  85. Downward J. Ras signalling and apoptosis. Curr Opin Genet Dev 1998b; 8: 49–54.

    Article  PubMed  CAS  Google Scholar 

  86. Collado M, Medema RH, Garcia-Cao I, Dubuisson ML, Barradas M, Glassford J, et al. Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kipl. J Biol Chem 2000; 275: 21960–21968.

    Article  PubMed  CAS  Google Scholar 

  87. Attardi LD, Jacks T. The role of p53 in tumour suppression: lessons from mouse models. Cell Mol Life Sci 1999; 55: 48–63.

    Article  PubMed  CAS  Google Scholar 

  88. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p161NK4a. Cell 1997; 88: 593–602.

    Article  PubMed  CAS  Google Scholar 

  89. Attardi LD, Lowe SW, Brugarolas J, Jacks T. Transcriptional activation by p53, but not induction of the p21 gene, is essential for oncogene-mediated apoptosis. EMBO J 1996; 15: 3702–3712.

    Google Scholar 

  90. Vogt M, Haggblom C, Yeargin, J, Christiansen-Weber T, Haas M. Independent induction of senescence by pl6INK4a and p21CIP1 in spontaneously immortalized human fibroblasts. Cell Growth Differ 1998; 9: 139–146.

    PubMed  CAS  Google Scholar 

  91. Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1999; 1: 20–26.

    Article  PubMed  CAS  Google Scholar 

  92. Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA. Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. Proc Natl Acad Sci USA 1999; 96: 1002–1007.

    Article  PubMed  CAS  Google Scholar 

  93. Guillouf C, Grana X, Selvakumaran M, De Luca A, Giordano A, Hoffman B, Liebermann DA. Dissection of the genetic programs of p53-mediated G1 growth arrest and apoptosis: blocking p53-induced apoptosis unmasks G1 arrest. Blood 1995; 85: 2691–2698.

    PubMed  CAS  Google Scholar 

  94. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 1995; 377: 552–557.

    Article  PubMed  CAS  Google Scholar 

  95. McCurrach ME, Connor TM, Knudson CM, Korsmeyer SJ, Lowe SW. bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc Natl Acad Sci USA 1997; 94: 2345–2349.

    Article  PubMed  CAS  Google Scholar 

  96. Aladjem MI, Spike BT, Rodewald LW, Hope TJ, Klemm M, Jaenisch R, Wahl GM. ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. Curr Biol 1998; 8: 145–155.

    Article  PubMed  CAS  Google Scholar 

  97. Corbet SW, Clarke AR, Gledhill S, Wyllie AH. P53-dependent and -independent links between DNA-damage, apoptosis and mutation frequency in ES cells. Oncogene 1999; 18: 1537–1544.

    Article  PubMed  CAS  Google Scholar 

  98. Strasser A, Harris AW, Jacks T, Cory S. DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bc1–2 [see comments]. Cell 1994; 79: 329–339.

    Article  PubMed  CAS  Google Scholar 

  99. Wyllie FS, Haughton MF, Bond JA, Rowson JM, Jones CJ, Wynford-Thomas D. S phase cell-cycle arrest following DNA damage is independent of the p53/p21(WAF1) signalling pathway. Oncogene 1996; 12: 1077–1182.

    PubMed  CAS  Google Scholar 

  100. Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM. Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J 1994; 13: 2124–2130.

    PubMed  CAS  Google Scholar 

  101. Missero C, Di Cunto F, Kiyokawa H, Koff A, Dotto GP. The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression. Genes Dey 1996; 10: 3065–3075.

    Article  CAS  Google Scholar 

  102. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995; 83: 993–1000.

    Article  PubMed  CAS  Google Scholar 

  103. Quelle DE, Cheng M, Ashmun RA, Sherr CJ. Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by pl6INK4a but not by the alternative reading frame protein p19ARF. Proc Natl Acad Sci USA 1997; 94: 669–673.

    Article  PubMed  CAS  Google Scholar 

  104. Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL. Disruption of the ARFMdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dey 1999; 13: 2658–2669.

    Article  CAS  Google Scholar 

  105. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 1998; 95: 8292–8297.

    Article  PubMed  CAS  Google Scholar 

  106. Tao W, Levine AJ. Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2mediated degradation of p53. Proc Natl Acad Sci USA 1999; 96: 3077–3080.

    Article  PubMed  CAS  Google Scholar 

  107. Tao W, Levine AJ. P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc Natl Acad Sci USA 1999; 96: 6937–6941.

    Article  PubMed  CAS  Google Scholar 

  108. Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dey 1998; 12: 2424–2433.

    Article  CAS  Google Scholar 

  109. Kamijo T, van de Kamp E, Chong MJ, Zindy F, Diehl JA, Sherr CJ, McKinnon PJ. Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function. Cancer Res 1999a; 59: 2464–2469.

    PubMed  CAS  Google Scholar 

  110. Kamijo T, Bodner S, van de Kamp E, Randle DH, Sherr CJ. Tumor spectrum in ARFdeficient mice. Cancer Res 1999b; 59: 2217–2222.

    PubMed  CAS  Google Scholar 

  111. Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p 19ARF. Cell 1997; 91: 649–659.

    Article  PubMed  CAS  Google Scholar 

  112. Sherr CJ. Tumor surveillance via the ARF-p53 pathway. Genes Dev 1998; 12: 2984–2991.

    Article  PubMed  CAS  Google Scholar 

  113. Sherr CJ, Weber JD. The ARF/p53 pathway. Curr Opin Genet Dev 2000; 10: 94–99.

    Article  PubMed  CAS  Google Scholar 

  114. Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 1996; 85: 721–732.

    Article  PubMed  CAS  Google Scholar 

  115. Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kipl)deficient mice. Cell 1996; 85: 733–744.

    Article  PubMed  CAS  Google Scholar 

  116. Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, et al. Mice lacking p27(Kipl) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 1996; 85: 707–720.

    Article  PubMed  CAS  Google Scholar 

  117. Latres E, Malumbres M, Sotillo R, Martin J, Ortega S, Martin-Caballero J, et al. Limited overlapping roles of P15(INK4b) and P18(INK4c) cell cycle inhibitors in proliferation and tumorigenesis. EMBO J 2000; 19: 3496–3506.

    Article  PubMed  CAS  Google Scholar 

  118. Chen P, Segil N. p27(Kip 1) links cell proliferation to morphogenesis in the developing organ of Corti. Development 1999; 126: 1581–1590.

    PubMed  CAS  Google Scholar 

  119. Lowenheim H, Furness DN, Kil J, Zinn C, Gultig K, Fero ML, et al. Gene disruption of p27(Kipl) allows cell proliferation in the postnatal and adult organ of corti. Proc Natl Acad Sci USA 1999; 96: 4084–4088.

    Article  PubMed  CAS  Google Scholar 

  120. Tong W, Kiyokawa H, Soos TJ, Park MS, Soares VC, Manova K, et al. The absence of p27Kipl, an inhibitor of G1 cyclin-dependent kinases, uncouples differentiation and growth arrest during the granulose → luteal transition. Cell Growth Differ 1998; 9: 787–794.

    PubMed  CAS  Google Scholar 

  121. Casaccia-Bonnefil P, Hardy RJ, Teng KK, Levine JM, Koff A, Chao MV. Loss of p27Kipl function results in increased proliferative capacity of oligodendrocyte progenitors but unaltered timing of differentiation. Development 1999; 126: 4027–4037.

    PubMed  CAS  Google Scholar 

  122. Casaccia-Bonnefil P, Tikoo R, Kiyokawa H, Friedrich V Jr, Chao MV, Koff A. Oligodendrocyte precursor differentiation is perturbed in the absence of the cyclin-dependent kinase inhibitor p27Kipl. Genes Dev 1997; 11: 2335–2346.

    Article  PubMed  CAS  Google Scholar 

  123. Durand B, Fero ML, Roberts JM, Raff MC. p27Kipl alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation. Curr Biol 1998; 8: 431–440.

    Article  PubMed  CAS  Google Scholar 

  124. Drissi, H., Hushka, D., Aslam, F., Nguyen, Q., Buffone, E., Koff, A., et al. The cell cycle regulator p27kip1 contributes to growth and differentiation of osteoblasts. Cancer Res 1999; 59: 3705–3711.

    PubMed  CAS  Google Scholar 

  125. Cordon-Cardo C, Koff A, Drobnjak M, Capodieci P, Osman I, Millard SS, et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J Natl Cancer Inst 1998; 90: 1284–1291.

    Article  PubMed  CAS  Google Scholar 

  126. Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, et al. Requirement for a functional Rb-1 gene in murine development. Nature 1992; 359: 328–330.

    Article  PubMed  CAS  Google Scholar 

  127. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA. Effects of an Rb mutation in the mouse. Nature 1992; 359: 295–300.

    Article  PubMed  CAS  Google Scholar 

  128. Lee EY, Chang CY, Hu N, Wang, YC, Lai CC, Herrup K, et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 1992; 359: 288–294.

    Article  PubMed  CAS  Google Scholar 

  129. Nikitin A, Lee WH. Early loss of the retinoblastoma gene is associated with impaired growth inhibitory innervation during melanotroph carcinogenesis in Rb+/− mice. Genes Dey 1996; 10: 1870–1879.

    Article  CAS  Google Scholar 

  130. Yamasaki L, Bronson R, Williams BO, Dyson NJ, Harlow E, Jacks T. Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/−) mice. Nat Genet 1998; 18: 360–364.

    Article  PubMed  CAS  Google Scholar 

  131. Williams BO, Remington L, Albert DM, Mukai S, Bronson RT, Jacks T. Cooperative turnorigenic effects of germline mutations in Rb and p53. Nat Genet 1994; 7: 480–484.

    Article  PubMed  CAS  Google Scholar 

  132. Brugarolas J, Bronson RT, Jacks T. p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells. J Cell Biol 1998; 141: 503–514.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Andrew Koff PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA, USA

    Antonio Giordano MD, PhD

  2. Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA

    Kenneth J. Soprano PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Koff, A. (2003). p27, A Prognostic Indicator Reflecting ...?. In: Giordano, A., Soprano, K.J. (eds) Cell Cycle Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-401-6_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-401-6_2

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-257-5

  • Online ISBN: 978-1-59259-401-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation