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Cell Cycle Inhibitors in Cancer Therapy pp 277–296Cite as

Mammalian CDK Inhibitors as Targets of Ubiquitinization in Cancer

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

Abstract

Within the last 10 years, several studies have clearly demonstrated that disruption of cell cycle control is one of the most frequent alterations in tumor cells leading to uncontrolled cell proliferation and tumor development (1). The commitment of eukaryotic cells to enter the DNA synthetic (S) phase of the cell cycle occurs at the so-called restriction point (R) late in G1 phase and is governed by a series of proteins called cyclins, which function as positive regulatory subunits of a family of cyclin-dependent protein kinases (CDKs) (2). Each cyclin binds to and activates specific CDKs thus controlling the progression of cells through the cell cycle. While CDKs are constitutively expressed with respect to cell cycle phases, cyclin levels oscillate, being regulated mainly at the transcriptional level but also by protein degradation via the ubiquitin proteasome pathway (1). The activity of cyclin/CDK complexes is further regulated by both positive and negative phosphorylation events (3), as well as their association with specific inhibitory proteins (2).

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References

  1. MacLachlan TK, Sang N, Giordano A. Cyclins, cyclin-dependent kinases and cdk inhibitors: implications in cell cycle control and cancer. Crit Rev Eukaryot Gene Expr 1995; 5: 127–156.

    Article  PubMed  CAS  Google Scholar 

  2. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dey 1995;9,1149–1163.

    Article  CAS  Google Scholar 

  3. Morgan DO. Principles of CDK regulation. Nature 1995;374:131–134.

    Article  PubMed  CAS  Google Scholar 

  4. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/cdk4. Nature 1993;366:704–707.

    Article  PubMed  CAS  Google Scholar 

  5. Hannon GJ, Beach D. p15INK4B is a potential effector of cell cycle arrest mediated by TGFI3. Nature 1994;371:257–261.

    Article  PubMed  CAS  Google Scholar 

  6. Hirai H, Roussel MF, Kato J, Ashmun RA, Sherr CJ. Novel INK4 proteins, p19 and p18, are specific inhibitors of cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 1995;15:2672–2681.

    PubMed  CAS  Google Scholar 

  7. Chan FKM, Zhang J, Chen L, Shapiro DN, Winoto A. Identification of a human mouse p19, a novel cdk4/cdk6 inhibitor with homology to p16INK4. Mol Cell Biol 1995;15:2682–2688.

    PubMed  CAS  Google Scholar 

  8. Xiong Y, Hannon H, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature 1993;366:701–704.

    Article  PubMed  CAS  Google Scholar 

  9. Bullrich F, MacLachlan T, 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 

  10. Lee MH, Reynisdottir I, Massague J. Cloning of p57kip2, a cylin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dey 1995;9:639–649.

    Article  CAS  Google Scholar 

  11. Medema R, Herrera RE, Lam, F, Weinberg RA. Growth suppression by p16INK4 requires functional retinoblastoma protein. Proc Natl Acad Sci USA 1995;92:6289–6293.

    Article  PubMed  CAS  Google Scholar 

  12. Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D. Inhibition of ras-induced proliferation and cellular transformation by p161NK4. Science 1995;267:249–252.

    Article  PubMed  CAS  Google Scholar 

  13. Parry D, Bates S, Mann DJ, Peters G. Lack of cyclinD-cdk complexes in Rb-negative cells correlates with high levels of p161NK4/MTS1 tumor suppressor gene product. EMBO J 1995;14:503–511.

    PubMed  CAS  Google Scholar 

  14. Guan K, Jenkins CW, Li Y, Nichols MA, Wu X, O’ Keefe CL, Matera AG, Xiong Y. Growth IN suppression by p18, a p16INK4-MTS1 and p14K4-MTS2related cdk6 inhibitor, correlates with wild type pRb function. Genes Dey 1994;8:2939–2952.

    Article  CAS  Google Scholar 

  15. Bardeesy N, Morgan J, Sinha M, Signoretti S, Srivastava S, Loda M, et al. Obligate roles for p16INK4A and p19(Arf)-p53 in the suppression of murine pancreatic neoplasia. Mol Cell Biol 2002;22:635–643.

    Article  PubMed  CAS  Google Scholar 

  16. Tannapfel A, Busse C, Weinans L, Benicke M, Katalinic A, Geissler F, et al. INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 2001;25:7104–7109.

    Article  CAS  Google Scholar 

  17. Martinez-Delgado B, Richart A, Garcia MJ, Robledo M, Osorio A, Cebrian A, et al. Hypermethylation of p16INK4A and p15INK4B genes as marker of disease in the follow-up of non-Hodgkin’s lymphomas. Br J Hematol 2000;109:97–103.

    Article  CAS  Google Scholar 

  18. Faderl S, Kantarjian HM, Manshouri T, Chan CY, Pierce S, Hays KJ, et al. The prognostic significance of p16INK4/p14ARF and p15INK4B deletions in adult acute lymphoblastic leukaemia. Clin Cancer Res 1999;5:1855–1861.

    PubMed  CAS  Google Scholar 

  19. Thullberg M, Bartkova J, Khan S, Hansen K, Ronnstrand L, Lukas J, et al. Distinct versus redundant properties among members of the INK4 family of cyclin-dependent kinase inhibitors. FEBS Lett 2000;470:161–166.

    Article  PubMed  CAS  Google Scholar 

  20. Gartel AL, Tyner AL. The growth regulatory role of p21 (wafl/cip1), in Molecular and Subcellular Biology. Vol. 20. Macieir-Coelho A, ed. Springer, Berlin, 1998, pp. 43–71.

    Google Scholar 

  21. Niculescu AB III, Chen X, Smeets M., Hengst L, Prives C, Reed SI. Effects of p2lcip1/ wafl at both the G1/S and the G2/M cell cycle transition: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol 1998;18:629–643.

    PubMed  CAS  Google Scholar 

  22. 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 

  23. Nevins JR. Towards an understanding of the functional complexity of the E2F and the retinoblastoma families Cell Growth Differ 1998;9:585–593.

    PubMed  CAS  Google Scholar 

  24. Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K, Mizutani S. Apoptosis inhibitory activity of cytoplasmic p21(cip 1 /wafl) in monocytic differentiation. EMBO J 1999;18:1223–1234.

    Article  PubMed  CAS  Google Scholar 

  25. Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 1994;370:220–223.

    Article  PubMed  CAS  Google Scholar 

  26. Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27kipl, 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 

  27. Fero ML, Rivkin M, Tasch M, Porter, P, Carow, CE, Firpo, E, et al. A syndrome of multi-organ hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27kipldeficient mice. Cell 1996;85:733–744.

    Article  PubMed  CAS  Google Scholar 

  28. 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 p27kip 1. Cell 1996;85:721–732.

    Article  PubMed  CAS  Google Scholar 

  29. Millard SS, Yan JS, Nguyen H, Pagano M, Kiyokawa H, Koff A. Enhanced ribosomal association of p27kipl mRNA is a mechanism contributing to accumulation during growth arrest. J Biol Chem 1997;272:7093–7098.

    Article  PubMed  CAS  Google Scholar 

  30. 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 

  31. Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR. Myc and Ras collaborate in inducing accumulation of active cyclin E/cdk2 and E2F. Nature (London) 1997;387:422–426.

    Article  CAS  Google Scholar 

  32. Reynisdottir I, Massague J. The subcellular locations of pl5INK4B and p27kipl coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dey 1997;11:492–503.

    Article  CAS  Google Scholar 

  33. Orend G, Hunter T, Ruoslahti E. Cytoplasmic displacement of cyclinE-cdk2 inhibitors p21Cipl and p27kipl in anchorage-independent cells. Oncogene 1998;16:2575–2583.

    Article  PubMed  CAS  Google Scholar 

  34. 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 

  35. Spirin KS, Simpson JF, Takeuchi S, Kawamata N, Miller CW, Koeffler HP. p27kipl mutation found in breast cancer. Cancer Res 1996;56:2400–2404.

    PubMed  CAS  Google Scholar 

  36. Matsuoka M, Edwards M, Bai C, Parker S, Zhang P, Baldini A, et al. p57k’P2, a structurally distinct member of the p21 cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dey 1995;9:650–662.

    Article  CAS  Google Scholar 

  37. Koi M, Johnson LA, Kalikan LM, Little PF, Nakamura Y, Feinberg AP. Tumor cell growth arrest caused by subchromosomal transferable DNA fragments from chromosome 11. Science 1993;260:361–364.

    Article  PubMed  CAS  Google Scholar 

  38. Thompson JS, Reese KJ, DeBaun MR, Perlman FJ, Feinberg AP. Reduced expression of the cyclin-dependent kinase inhibitor gene p57kip2 in Wilm’s tumor. Cancer Res 1996; 56: 5723–5727.

    PubMed  CAS  Google Scholar 

  39. Lai S, Goepfert H, Gillenwater AM, Luna MA, El-Naggar AK. Loss of imprinting and genetic alterations of the cyclin-dependent kinase inhibitor p57kip2 gene in head and neck squamous cell carcinoma. Clin Cancer Res 2000;6:3172–3176.

    PubMed  CAS  Google Scholar 

  40. Feinberg AP. Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction. Cancer Res 1999;59 (7 Suppl):1743s-1746s.

    CAS  Google Scholar 

  41. Stiegler P, Kasten M, Giordano A. The RB family of cell cycle regulatory factors. J Cell Biochem 1998;30/31:30–36.

    Article  Google Scholar 

  42. Slansky JE, Farnham Pi. Introduction to the E2F family: protein structure and gene regulation. Curr Top Microbiol Immunol 1996;208:1–30.

    Article  PubMed  CAS  Google Scholar 

  43. La Baer J, Garret MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, et al. New functional activities for the p21 family of CDK inhibitors. Genes Dey 1997;11:847–862.

    Article  Google Scholar 

  44. Wu X, Levine A. p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci USA 1994;91:3602–3606.

    Article  PubMed  CAS  Google Scholar 

  45. Fong LY, Nguyen VT, Farber JL, Huebner K, Magee PN. Early deregulation of the p 16INK4acyclinDl/cyclin-dependent kinase 4-retinoblastoma pathway in cell proliferation-driven esophageal tumorigenesis in zinc-deficient rats. Cancer Res 2000;60:4589–4595.

    PubMed  CAS  Google Scholar 

  46. Alexander K, Hinds PW. Requirement for p27(KIP1) in retinoblastoma protein-mediated senescence. Mol Cell Biol 2001;21(11):3616–3631.

    Article  PubMed  CAS  Google Scholar 

  47. Baldi A, De Luca A, Claudio PP, Baldi F, Giordano GG, Tommasino M, et al. The RB2/ p130 gene product is a nuclear protein whose phosphorylation is cell cycle regulated. J Cell Biochem 1995;59:402–408.

    Article  PubMed  CAS  Google Scholar 

  48. Nevins J. Toward an understanding of the functional complexity of the E2F and retinoblastoma families. Cell Growth Differ 1998;9:585–593.

    PubMed  CAS  Google Scholar 

  49. Howard, C M, Claudio, P. P, De Luca, A, Stiegler, P, Jori, FP, Safdar NM, et al. Inducible pRb2/p130 expression and growth-suppressive mechanisms: evidence of a pRb2/p130, p271(’P1, and cyclin E negative feedback regulatory loop. Cancer Res 2000;60:2737–2744.

    CAS  Google Scholar 

  50. Zhang D, Vuocolo S, Masciullo V, Sava T, Giordano A, Soprano DR, Soprano KJ. Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression. Onco gene 2001;20(55):7935–7944.

    Article  CAS  Google Scholar 

  51. King R, Deshaies R, Peters J, Kirschner M. How proteolysis drive the cell cycle. Science 1996;274:1652–1659.

    Article  PubMed  CAS  Google Scholar 

  52. Pagano, M. Cell cycle regulation by the ubiquitin pathway. FASEB J 1997;11(13): 1067–1075.

    PubMed  CAS  Google Scholar 

  53. Ciechanover A, Schwartz AL. The ubiquitin proteasome pathway: the complexity and myriad functions of proteins death. Proc Natl Acad Sci USA 1998;95:2727–2730.

    Article  PubMed  CAS  Google Scholar 

  54. Glotzer MA, Murray A, Kirschner M. Cyclin is degraded by the ubiquitin pathway. Nature 1991;349:132–138.

    Article  PubMed  CAS  Google Scholar 

  55. Maki C, Hulbregtse J, Howley P. In vivo ubiquitination and proteasome-mediated degradation of p53. Cancer Res 1996;56:2649–2654.

    PubMed  CAS  Google Scholar 

  56. Ciechanover A, Orian A, Schwartz AL. The ubiquitin-mediated proteolitic pathway: mode of action and clinical implications. J Cell Biochem (suppl) 2000;34:40–51.

    Article  CAS  Google Scholar 

  57. Ciechanover A, Hod Y, Hershko A. A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun 1978; 81:1100–1105.

    Article  Google Scholar 

  58. Wilkinson KD, Urban MK, Haas AL. Ubiquitin is the ATP-dependent proteolysis factor of rabbit reticulocytes. J Biol Chem 1980;255,7529–7532.

    PubMed  CAS  Google Scholar 

  59. Goldstein G, Scheid M, Hammerling U, Schlesinger DH, Niall HD, Boyse EA. Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proc Natl Acad Sci USA 1975;72(1):11–15.

    Article  PubMed  CAS  Google Scholar 

  60. Hough R, Pratt G, Rechsteiner M. Ubiquitin-lysozime conjugates. Identification and characterization of an ATP-dependent protease from rabbit reticulocyte lysates. J Biol Chem 1986;261:2400–2408.

    PubMed  CAS  Google Scholar 

  61. Varshaysky A. The N-end rule: functions, mysteries, uses. Proc Natl Acad Sci USA 1996;93:12142–12149.

    Article  Google Scholar 

  62. Lanker S, Valdivieso MH, Wittenberg C. Rapid degradation of the G1 cyclin C1n2 induced by CDK-dependent phosphorylation. Science 1996;271:1597–1601.

    Article  PubMed  CAS  Google Scholar 

  63. Yaglom J, Linskens HK, Sadias S, Rubin DM, Futcher B, Finley D. p34-Cdc28-mediated control of Cln3 degradation. Mol Cell Biol 1995;15:731–741.

    PubMed  CAS  Google Scholar 

  64. Verma R, Annan R, Huddleston M, Can S, Reynard G, Deshaies R. Phosphorylation of Sic 1 by G1 Cdk required for its degradation and entry into S phase. Science 1997;278:455–460.

    Article  PubMed  CAS  Google Scholar 

  65. Diehl J, Zindy F, Sherr C. Inhibition of cyclin D1 phosphorylation on threonine 286 prevent its rapid degradation via the ubiquitin proteasome pathway. Genes Dev 1997;11:957–972.

    Article  PubMed  CAS  Google Scholar 

  66. Clurman BE, Sheaff RJ, Thress K, Groudine M, Roberts JM. Turnover of cyclin E by the ubiquitin proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev 1996;10:1979–1990.

    CAS  Google Scholar 

  67. Carrano AC, Eytan E, Hersko A, Pagano M. SKP2 is required for ubiquitin mediated degradation of the CDK inhibitor p27kipl. Nature Cell Biol 1999;1:193–199.

    Article  PubMed  CAS  Google Scholar 

  68. Yaron A, Gonen H, Alkalay I, Hatzubai A, Jung S, Beyth S, et al. Inhibition of NF-KB cellular function via specific targeting of the IkBa-ubiquitin ligase. EMBO J 1997;16:6486–6494.

    Article  PubMed  CAS  Google Scholar 

  69. Rubinfeld B, Robbins P, El-gamil M, Albert I, Porfiri E, Polakis P. Stabilization of (3-catenin by genetic defects in melanoma cell lines. Science 1997;275:1790–1792.

    Article  PubMed  CAS  Google Scholar 

  70. Nishizawa M, Furuno N, Okazaki K, Tanaka H, Ogawa Y, Sagata N. Degradation of Mos by tye N-terminalproline (Pro2)-dependent unbiquitin pathway on fertilization of Xenopus eggs: possible significance of natural selection for Pro2 in Mos. EMBO J 1993;12:4021–4027.

    PubMed  CAS  Google Scholar 

  71. Dimmeler S, Breithschopf K, Haendeler J, Zeiher AM. Dephosphorylation targets bc1–2 for ubiquitin dependent degradation: a link between the apoptosome and the proteasome pathway. J Exp Med 1999;189:1815–1822.

    Article  PubMed  CAS  Google Scholar 

  72. Visintin R, Prinz S, Amon A. CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis. Science 1997;278:460–463.

    Article  PubMed  CAS  Google Scholar 

  73. Zhu Y, Carrol M, Papa FR, Hochstrasser M, D’Andrea AD. DUB-1, a deubiquitinating enzyme with growth-suppressing activity. Proc Natl Acad Sci USA 1996;93:3275–3279.

    Article  PubMed  CAS  Google Scholar 

  74. Blagosklonny MV, Wu GS, Omura S, El-Deiry WS. Proteasome-dependent regulation of p21Waf1ic’P’ expression. Biophys Res Comm 1996;227;564–569.

    Article  CAS  Google Scholar 

  75. Maki CG, Huibregtse JM, Howley PM. In vivo ubiquitination and proteasome mediated degradation of p53. Cancer Res 1996;56:2649–2654.

    PubMed  CAS  Google Scholar 

  76. Maki CG, Howley PM. Ubiquitination of p53 and p21 is differentially affected by ionizing and UV radiation. Mol Cell Biol 1997;17:355–363.

    PubMed  CAS  Google Scholar 

  77. Cayrol C, Ducommun B. Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21. Oncogene 1998;12,17(19):2437–2444.

    Google Scholar 

  78. Rousseau D, Cannella D, Boulaire J, Fitzgerald P, Fotedar A, Fotedar R. Growth inhibition by CDK-cyclin and PCNA binding domains of p21 occurs by distinct mechanisms and is regulated by ubiquitin proteasome pathway. Oncogene 1999;18:3290–3302.

    Article  PubMed  CAS  Google Scholar 

  79. Yu Z, Gervais JLM., Zhang H. Human CUL-1 associates with the SKPI/SKP2 com-plex and regulates p21cIPInvAFI and cyclin D proteins. Proc Natl Acad Sci USA 1998;95: 11324–11329.

    Article  PubMed  CAS  Google Scholar 

  80. Fukuchi K, Tomoyasu S, Nakamaki T, Tsuruoka N, Gomi K. DNA damage induces p21 protein expression by inhibiting ubiquitination in ML-1 cells. Biochim Biophys Acta 1998;1404:405–411.

    Article  PubMed  CAS  Google Scholar 

  81. Sheaff RJ, Singer JD, Swanger J, Smitherman M, Roberts JM, Clurman BE. Proteosomal turnover of p2101P1 does not require p21¡ãIPl ubiquitination. Mol Cell 2000;5:403–410.

    Article  PubMed  CAS  Google Scholar 

  82. Hirai H, Roussel MF, Kato J, Ashmun RA, Sherr CJ. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 1995;15:2672–2681.

    PubMed  CAS  Google Scholar 

  83. Thullberg M, Bartek J, Lukas J. Ubiquitin/proteasome-mediated degradation of p19INK4d determines its periodic expression during the cell cycle. Onco gene 2000;19:2870–2876.

    Article  CAS  Google Scholar 

  84. Yan Y, Frisen J, Lee MH, Massague J, Barbacid M. Ablation of the cdk inhibitor p57k1P2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dey 1997;11(8):973–983.

    Article  CAS  Google Scholar 

  85. Nishimori S, Tanaka Y, Chiba T, Fujii M, Imamura T, Miyazono K, et al. Smad-mediated transcription is required for transforming growth factor-beta 1-induced p57(Kip2) proteolysis in osteoblastic cells. JBiol Chem 2001;6,276(14):10700–10705.

    Google Scholar 

  86. Urano T, Yashiroda H, Muraoka M, Tanaka K, Hosoi T, Inoue S, et al. p57(Kip2) is degraded through the proteasome in osteoblasts stimulated to proliferation by transforming growth factor betal. J Biol Chem 1999 Apr 30;274(18):12197–12200.

    Article  PubMed  CAS  Google Scholar 

  87. 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 p27kIPI. Science 1995;269:682–685.

    Article  PubMed  CAS  Google Scholar 

  88. Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27k1P1. EMBO J 1997;16(17):5334–5344.

    Article  PubMed  CAS  Google Scholar 

  89. Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE. Cyclin E/cdk2 is a regulator of p27k1P1. Genes Dey 1997;11:1464–1478.

    Article  CAS  Google Scholar 

  90. Tsvetkov LM, Yeh K, Lee S, Sun H, Zhang H. p271up1 ubiquitination and degradation is regulated by the SCFskP2 complex through phosphorylated Thr187 in p27. Curr Biol 1999;9:661–664.

    Article  PubMed  CAS  Google Scholar 

  91. Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27k1P1. Nat Cell Biol 1999;1(4):193–199.

    Article  PubMed  CAS  Google Scholar 

  92. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hersko A, Pagano M. Ubiquitination of p27 is regulated by cdk dependent and trimeric complex formation. Genes Dey 1999;13(9):1181–1189.

    Article  CAS  Google Scholar 

  93. Sutterluty H, Chatelain E, Marti A, Wirbelauer C., Senften M, Muller U, Krek W. p45SKP2 promotes p27klP1degradation and induces S phase in quiescent cells. Nat Cell Biol 1999;1(4):207–214.

    Article  PubMed  CAS  Google Scholar 

  94. Podust NV, Brownell JE, Gladysheva TB, Luo R, Wang C, Coggins MB, et al. A Nedd 8 conjugation pathway is essential for proteolytic targeting of p27k`P1 by ubiquitination. Proc Natl Acad Sci USA 2000;97,9:4579–4584.

    Article  PubMed  CAS  Google Scholar 

  95. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent kinase inhibitor p27k1P1 is instigated by Jabl. Nature 1999;398:160–165.

    Article  PubMed  CAS  Google Scholar 

  96. Hu W, Bellone CJ, Baldassarre JJ. RhoA stimulates p27k1P1 degradation through its regulation of cyclin E/cdk2 activity. J Biol Chem 1999;274:3396–3401.

    Article  PubMed  CAS  Google Scholar 

  97. Kawada M, Yamagoe S, Murakami Y, Suzuki K, Mizuno S, Uehara Y. Induction of p27141 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene 1997;15:629–637.

    Article  PubMed  CAS  Google Scholar 

  98. O’Hagan RC, Ohh M, David G, de Alboran IM, Alt FW, Kaelin WG, De Pinho RA. Myc enhanced expression of Cull promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes Dey 2000;14,17:2185–2191.

    Article  Google Scholar 

  99. Borriello A, Della Pietra V, Criscuolo M, Oliva A, Tonin GP, Iolascon A, et al. p271uP1 accumulation is associated with retinoic-induced neuroblastoma differentiation: evidence of a decreased proteasome-dependent degradation. Onco gene 2000;19:51–60.

    Article  CAS  Google Scholar 

  100. Mammilapalli R, Gavrilova N, Mihaylova VT, Tsyetkov LM, Wu H, Zhang H, Sun H. PTEN regulates the ubiquitin-dependent degradation of the cdk inhibitor p27kipl through the ubiquitin 3 ligase SCF (SKP2). CurrBiol 2001;11,4:263–267.

    Article  Google Scholar 

  101. Sgambato A, Cittadini A, Faraglia B, Weinstein IB. Multiple functions of p27kipl and its alterations in tumor cells: a review. J Cell Physiol 2000;183:18–27.

    Article  PubMed  CAS  Google Scholar 

  102. Zhang H, Kobayashi R, Galaktionov K, Beach D. p19Skpl and p45Skp2 are essential elements of the cyclinA-cdk2 S phase kinase. Cell 1995;82:915–925.

    Article  PubMed  CAS  Google Scholar 

  103. Nakayama K, Nagahama K, Minamishima YA, Matsumoto M, Nakamichi I, Kitagawa K, et al. Targeted disruption of SKP2 results in accumulation of cyclin E and p271 P1 polyploidy and centrosome overduplication. EMBO J 2000;19(9):2069–2081.

    CAS  Google Scholar 

  104. Hara T, Kamura T, Nakayama K, Oshikawa K, Hatakeyama S, Nakayama K. Degradation of p271UP1 at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem 2001;276(52):48937–48943.

    Article  PubMed  CAS  Google Scholar 

  105. Piva R, Cancell I, Cavalla P, Bortolotto S, Dominguez J, et al. Proteasome dependent degradation of p271dP1 in gliomas. J Neuropathol Exp Neurol 1999;58:691–696.

    Article  PubMed  CAS  Google Scholar 

  106. Esposito V, Baldi A, De Luca A, Groger AM, Loda M., Giordano GG, et al. Prognostic role of the cyclin dependent kinase inhibitor p27 in non small cell lung cancer. Cancer Res 1997;57:3381–3385.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  109. 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 

  110. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999;59: 2615–2622.

    PubMed  CAS  Google Scholar 

  111. Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 1999;5:2638–2645.

    PubMed  CAS  Google Scholar 

  112. Murray RZ, Norbury C. Proteasome inhibitors as anti-cancer agents. Anticancer Drugs 2000;11:407–417.

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. Valeria Masciullo MD, PhD
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  2. Kenneth J. Soprano PhD
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  3. Antonio Giordano MD, PhD
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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

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© 2003 Springer Science+Business Media New York

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Masciullo, V., Soprano, K.J., Giordano, A. (2003). Mammalian CDK Inhibitors as Targets of Ubiquitinization in Cancer. 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_11

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  • DOI: https://doi.org/10.1007/978-1-59259-401-6_11

  • 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

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