The Insulin-like Growth Factor Axis in Cell Cycle Progression

Abstract

Emerging evidence suggests that members of the Insulin-like Growth Factors (IGFs) family, including IGF-I, IGF-II, the IGF-I receptor (IGF-IR), and the IGF-binding proteins (IGFBPs) play a central role in the development and progression of cancer. Cancer cells exhibit an increased and deregulated proliferative activity. Abnormalities in many positive and negative modulators of the cell cycle are also frequent in many cancer types. Recent advances in the understanding of cell-cycle control mechanisms have been applied to outline the molecular mechanism through which IGFs regulate cell cycle progression. In this review, we will provide a brief overview of the role of the IGF system as a regulator of some components of the cell cycle.

Key words

Cancer - G1/S phase - IGF-IR - Signaling - Cell growth

References

• 1 Sullivan K A, Castle V P, Hanash S M, Feldman E L. Insulin-like growth factor II in the pathogenesis of human neuroblastoma.  Am J Pathol. 1995;  147 1790-1798
• 2 Toretsky J A, Helman L J. Involvement of IGF-II in human cancer.  J Endocrinol. 1996;  149 367-372
• 3 Sachdev D, Yee D. The IGF system and breast cancer.  Endocr Relat Cancer. 2001;  8 197-209
• 4 Moschos S J, Mantzoros C S. The role of the IGF system in cancer: from basic to clinical studies and clinical applications.  Oncology. 2002;  63 317-332
• 5 Ma J, Pollak M N, Giovannuci E, Chan J M, Tao Y, Hennekens C H, Stampfer M J. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3.  J Natl Cancer Ins. 1999;  91 620-625
• 6 Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer.  Nat Rev Cancer. 2001;  1 222-231
• 7 Sandhu C, Slingerland J. Deregulation of the cell cycle in cancer.  Cancer Detect Prev. 2000;  24 107-118
• 8 Sherr C J. Cancer and cell cycles revisited.  Cancer Res. 2000;  60 3689-3695
• 9 LeRoith D, Werner H, Beitner-Johnson D, Roberts C T Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor.  Endocr Rev. 1995;  16 143-163
• 10 Clemmons D R. Insulin-like growth factor binding proteins and their role in controlling IGF actions.  Cytokine Growth Factor Rev. 1997;  8 45-62
• 11 Baker J, Liu J P, Robertson E J, Efstradiatis A. Role of insulin-like growth factors in embryonic and postnatal growth.  Cell. 1993;  75 73-82
• 12 Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-Meek S, Dalton D, Gillett N, Stewart T A. IGF-I is required for normal embryonic growth in mice.  Genes Dev. 1993;  7 2609-2617
• 13 Yakar S, Liu J L, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I.  Proc Natl Acad Sci U S A. 1999;  96 7324-7329
• 14 Sjogren K, Liu J L, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Tornell J, Isaksson O G, Jansson J O, Ohlsson C. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice.  Proc Natl Acad Sci U S A. 1999;  96 7088-7092
• 15 DeChiara T, Efstratiadis A, Robertson E. A growth deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting.  Nature. 1990;  345 78-80
• 16 Baxter R C. Characterization of the acid-labile subunit of the growth hormone-dependent insulin-like growth factor binding protein complex.  J Clin Endocrinol Metab. 1988;  67 65-272
• 17 Boisclair Y R, Hurst K R, Ueki I, Tremblay M L, Ooi G T. Regulation and role of the acid-labile subunit of the 150-kilodalton insulin-like growth factor complex in the mouse.  Pediatr Nephrol. 2000;  14 562-566
• 18 Ferry R J Jr, Katz L E, Grimberg A, Cohen P, Weinzimer S A. Cellular actions of insulin-like growth factor binding proteins.  Horm Metab Res. 1999;  31 192-202
• 19 Arai T, Busby W Jr, Clemmons D R. Binding of insulin-like growth factor (IGF) I or II to IGF-binding protein-2 enables it to bind to heparin and extracellular matrix.  Endocrinology. 1996;  137 4571-4575
• 20 Delbe J, Blat C, Desauty G, Harel L. Presence of IDF45 (mlGFBP-3) binding sites on chick embryo fibroblasts.  Biochem Biophys Res Commun. 1991;  179 495-501
• 21 Valentinis B, Bhala A, DeAngelis T, Baserga R, Cohen P. The human insulin-like growth factor (IGF) binding protein-3 inhibits the growth of fibroblasts with a targeted disruption of the IGF-I receptor gene.  Mol Endocrinol. 1995;  9 361-367
• 22 Baxter R C. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities.  Am J Physiol Endocrinol Metab. 2000;  278 E967-976
• 23 Pavelic K, Bukovic D, Pavelic J. The role of insulin-like growth factor 2 and its receptors in human tumors.  Mol Med. 2002;  8 771-780
• 24 McKinnon T, Chakraborty C, Gleeson L M, Chidiac P, Lala P K. Stimulation of human extravillous trophoblast migration by IGF-II is mediated by IGF type 2 receptor involving inhibitory G protein(s) and phosphorylation of MAPK.  J Clin Endocrinol Metab. 2001;  86 3665-3675
• 25 Minniti C P, Kohn E C, Grubb J H, Sly W S, Oh Y, Muller H L, Rosenfeld R G, Helman L J. The insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptor mediates IGF-II-induced motility in human rhabdomyosarcoma cells.  J Biol Chem. 1992;  267 9000-9004
• 26 Ullrich A, Gray A, Tam A W, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le Bon T, Kathuria S, Chen E. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity.  Embo J. 1986;  10 2503-2512
• 27 Hongo A, D’Ambrosio C, Miura M, Morrione A, Baserga R. Mutational analysis of the mitogenic and transforming activities of the insulin-like growth factor I receptor.  Oncogene. 1996;  12 1231-1238
• 28 Li S, Resnicoff M, Baserga R. Effect of mutations at serines 1280 - 1283 on the mitogenic and transforming activities of the insulin-like growth factor I receptor.  J Biol Chem. 1996;  271 12 254-60.
• 29 Miura M, Surmacz E, Burgaud J L, Baserga R. Different effects on mitogenesis and transformation of a mutation at tyrosine 1251 of the insulin-like growth factor I receptor.  J Biol Chem. 1995;  270 22 639-44
• 30 Blakesley V A, Koval A P, Stannard B S, Scrimgeour A, LeRoith D. Replacement of tyrosine 1251 in the carboxyl terminus of the insulin-like growth factor-I receptor disrupts the actin cytoskeleton and inhibits proliferation and anchorage-independent growth.  J Biol Chem. 1998;  273 18 411-22
• 31 Sun X J, Rothenberg P, Kahn C R, Backer J M, Araki E, Wilden P A, Cahill D A, Goldstein B J, White M F. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.  Nature. 1991;  352 73-77
• 32 Patti M E, Sun X J, Bruening J C, Araki E, Lipes M A, White M F, Kahn C R. 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice.  J Biol Chem. 1995;  270 24 670-24 673
• 33 Lavan B E, Fantin V R, Chang E T, Lane W S, Keller S R, Lienhard G E. A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family.  J Biol Chem. 1997;  272 21 403-21 407
• 34 Lavan B E, Lane W S, Lienhard G E. The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family.  J Biol Chem. 1997;  272 1439-11 443
• 35 Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci P G. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction.  Cell. 1992;  70 93-104
• 36 Holgado-Madruga M, Emlet D R, Moscatello D K, Godwin A K, Wong A J. A Grb2-associated docking protein in EGF- and insulin-receptor signalling.  Nature. 1996;  379 560-564
• 37 Hermanto U, Zong C S, Li W, Wang L H. RACK1, an insulin-like growth factor I (IGF-I) receptor-interacting protein, modulates IGF-I-dependent integrin signaling and promotes cell spreading and contact with extracellular matrix.  Mol Cell Biol. 2002;  22 2345-2365
• 38 Ligensa T, Krauss S, Demuth D, Schumacher R, Camonis J, Jaques G, Weidner K M. A PDZ domain protein interacts with the C-terminal tail of the insulin-like growth factor-1 receptor but not with the insulin receptor.  J Biol Chem. 200;  276 33 419-33 427
• 39 Moodie S A, Alleman-Sposeto J, Gustafson T A. Identification of the APS protein as a novel insulin receptor substrate.  J Biol Chem. 1999;  274 11 186-11 193
• 40 Cai D, Dhe-Paganon S, Melendez P A, Lee J, Shoelson S E. Two New Substrates in Insulin Signaling, IRS5/DOK4 and IRS6/DOK5. J. Biol.  Chem. 2003;  278 25 323-25 330
• 41 Lawlor M A, Alessi D R. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?.  J Cell Sci. 2001;  114 2903-2910
• 42 Burgering B M, Medema R H. Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty.  J Leukoc Biol. 2003;  73 689-701
• 43 Maehama T, Taylor G S, Dixon J E. PTEN and myotubularin: novel phosphoinositide phosphatases.  Annu Rev Biochem. 2001;  70 247-79
• 44 Coolican S A, Samuel D S, Ewton D Z, McWade F J, Florini J R. The mitogenic and myogenic actions of insulin-like growth factors utilize distinct signaling pathways.  J Biol Chem. 1997;  272 6653-6662
• 45 Valverde A M, Teruel T, Lorenzo M, Benito M. Involvement of Raf-1 kinase and protein kinase C zeta in insulin-like growth factor I-induced brown adipocyte mitogenic signaling cascades: inhibition by cyclic adenosine 3’,5’-monophosphate.  Endocrinology. 1996;  137 3832-3841
• 46 Kuemmerle J F. IGF-I elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase.  Am J Physiol Gastrointest Liver Physiol. 2003;  284 G411-G422
• 47 Kuemmerle J F, Bushman T L. IGF-I stimulates intestinal muscle cell growth by activating distinct PI 3-kinase and MAP kinase pathways.  Am J Physiol. 1998;  275 G151-G158
• 48 Dufourny B, Alblas J, van Teeffelen H A, van Schaik F M, van der Burg B, Steenbergh P H, Sussenbach J S. Mitogenic signaling of insulin-like growth factor I in MCF-7 human breast-cancer cells requires phosphatidylinositol 3-kinase and is independent of mitogen-activated protein kinase.  J Biol Chem. 1995;  23 589-23 597
• 49 Misawa A, Hosoi H, Arimoto A, Shikata T, Akioka S, Matsumura T, Houghton P J, Sawada T. N-Myc induction stimulated by insulin-like growth factor I through mitogen-activated protein kinase signaling pathway in human neuroblastoma cells.  Cancer Res. 2000;  60 64-69
• 50 Misawa A, Hosoi H, Tsuchiya K, Sugimoto T. Rapamycin inhibits proliferation of human neuroblastoma cells without suppression of MycN.  Int J Cancer. 2003;  104 233-237
• 51 Thomas G. The S6 kinase signaling pathway in the control of development and growth.  Biol Res. 2002;  35 305-313
• 52 Pearson R B, Thomas G. Regulation of p70s6k/p85s6k and its role in the cell cycle.  Prog Cell Cycle Res. 1995;  1 21-32
• 53 Morgan D O. Cyclin-dependent kinases: engine, clocks, and microprocessors.  Annu Rev Cell Dev Biol. 1997;  13 261-291
• 54 Adams P D. Regulation of the retinoblastoma tumor suppressor protein by cyclin/CDKs.  Biochim Piophys Acta. 2001;  1471 123-133
• 55 Hunter T, Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age.  Cell. 1994;  79 573-582
• 56 Grana X, Reddy P. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs).  Oncogene. 1995;  11 211-219
• 57 Harbour J W, Dean D C. The pRb/E2F pathway: expanding roles and emerging paradigms.  Gene Dev. 2000;  14 2393-2409
• 58 Nigg E A. Cyclin-dependent kinase 7: at the cross-roads of transcription, DAN repair and cell cycle control?.  Curr Opin Cell Biol. 1996;  8 312-317
• 59 Ekholm S V, Reed S I. Regulation of G1, cyclin dependent kinase in the mammalian cell cycle.  Curr Opin Cell Biol. 2000;  12 676-684
• 60 Roussel M F. The INK4 family of cell cycle inhibitors in cancer.  Oncogene. 1999;  18 5311-5317
• 61 Nakayama K. Cip/Kip cyclin-dependent kinase inhibitors: brakes of the cell cycle engine during development.  Bioessays. 1998;  20 1020-1029
• 62 Sherr C J, Roberts J M. CDK inhibitors: positive and negative regulators of G1-phase progression.  Genes Dev. 1999;  13 1501-1512
• 63 Slingerland J, Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer.  J Cell Physiol. 2000;  183 10-17
• 64 Rosenthal S, Cheng Z Q. Opposing early and late effects of insulin-like growth factor I on differentiation and the cell cycle regulatory retinoblastoma protein in skeletal myoblasts.  Proc Natl Acad sci USA. 1995;  92 10 307-10 311
• 65 Dupont J, Karas M, LeRoith D. The potentiation of estrogen on insulin-like growth factor I action in MCF-7 human breast-cancer cells includes cell cycle components.  J Biol Chem. 2000;  275 35 893-35 901
• 66 Dufourny B, van Teeffelen H A, Hamelers I H, Sussenbach J S, Steenbergh P H. Stabilization of cyclin D1mRNA via the phosphatidylinositol 3-kinase pathway in MCF-7 human breast-cancer cells.  J Endocrinol. 2000;  166 329-338
• 67 Muise-Helmericks R C, Grimes H L, Bellacosa A, Malstrom S E, Tsichlis P N, Rosen N. Cyclin D expression is controlled post-transcriptionally via a phosphatidtlinositol 3-kinase/Akt-dependent pathway.  J Biol Chem. 1998;  273 29 864-29 872
• 68 Diehl J A, Cheng A M, Roussel M F, Sherr C J. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.  Genes Dev. 1998;  12 3499-3511
• 69 Hamelers I H, van Schaik R F, Sipkema J, Sussenbach J S, Steenbergh P H. Insulin-like growth factor I triggers nuclear accumulation of cyclin D1 in MCF-7S breast-cancer cells.  J Biol Chem. 2002;  277 47 645-47 652
• 70 Zhu X, Kwon C H, Schlosshauer P W, Ellenson L H, Baker S J. PTEN induces G(1) cell cycle arrest and decreases cyclin D3 levels in endometrial carcinoma cells.  Cancer Res. 2001;  61 4569-4575
• 71 Gottschalk A R, Basila D, Wong M, Dean N M, Brandts C H, Stokoe D, Haas-Kogan D A. p27Kip1 is required for PTEN-induced G1 growth arrest.  Cancer Res. 2001;  61 2105-2111
• 72 Ramaswamy S N, Nakamura I, Sansal I, Bergeron L, Sellers W R. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR.  Cancer Cell. 2002;  2 81-91
• 73 Cheng M, Sexl V, Sherr C J, Roussel M F. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).  Proc Natl Acad Sci U S A. 1998;  95 1091-1096
• 74 Weber J D, Hu W, Jefcoat S C Jr, Raben D M, Baldassare J J. Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27.  J Biol Chem. 1997;  272 32 966-32 971
• 75 Lavoie J N, L’Allemain G, Brunet A, Muller R, Pouyssegur J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway.  J Biol Chem. 1996;  271 20 608-20 616
• 76 Weng L P, Smith W M, Brown J L, Eng C. PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model.  Hum Mol Genet. 2001;  10 605-616
• 77 Brisken C, Ayyannan A, Nguyen C, Heineman A, Reinhardt F, Tan J, Dey S K, Dotto G P, Weinberg R A, Jan T. IGF-II is a mediator of prolactin-induced morphogenesis in the breast.  Dev Cell. 2002;  3 877-887
• 78 Zhang W, Lee J C, Kumar S, Gowen M. ERK pathway mediates the activation of Cdk2 in IGF-I-induced proliferation of human osteosarcoma MG-63 cells.  J Bone Miner Res. 1999;  14 528-535
• 79 Machida S, Spangenburg E E, Booth F W. Forkhead transcription factor FoxO1 transduces insulin-like growth factor’s signal to p27KIP1 in primary skeletal muscle satellite cells.  Journal of Cellular Physiology. 2003;  196 523-531
• 80 Spangenburg E E, Chakravarthy M V, Booth F W. p27Kip1: a key regulator of skeletal muscle satellite cell proliferation.  Clin Orthop. 2002;  403 S221-227
• 81 Ewton D Z, Kansra S, Lim S, Friedman E. Insulin-like growth factor-I has a biphasic effect on colon carcinoma cells through transient inactivation of forkhead1, initially mitogenic, then mediating growth arrest and differentiation.  Int J Cancer. 2002;  98 665-673
• 82 Medema R H, Kops G J, Bos J L, Burgenring B M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.  Nature. 2000;  404 782-787
• 83 Dijkers P F, Medema R H, Pals C, Banerji L, Thomas N S, Lam E W, Burgering B M, Raaijmakers J A, Lammers J W, Koenderman L, Coffer P J. Forkhead transcription f actor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1).  Mol Cell Biol. 2000;  20 9138-9148
• 84 Mamillapalli R, Gavrilova N, Mihaylova V T, Tsvetkov L M, Wu H, Zhang H, Sun H. PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2).  Curr Biol. 2001;  11 263-267
• 85 Pagano M, Tam S W, Theodoras A M, Beer-Romero P, Del Sal G, Chau V, Yew P R, Draetta G F, Rolfe M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27.  Science. 1995;  269 682-685
• 86 Fujita N, Sato S, Katayama K, Tsuruo T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14 - 3-3 and cytoplasmic localization.  J Biol Chem. 2002;  277 28 706-28 713
• 87 Carrano A C, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.  Nat Cell Biol. 1999;  1 193-199
• 88 Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama K I. Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export.  J Biol Chem. 2002;  277 14 355-143 558
• 89 Kanter-Lewensohn L, Dricu A, Girnita L, Wejde J, Larsson O. Expression of insulin-like growth factor-1 receptor (IGF-IR) and p27Kip1 in melanocytic tumors: a potential regulatory role of IGF-I pathway in distribution of p27Kip1 between different cyclins.  Growth Factors. 2000;  17 193-202
• 90 von Harsdorf R, Hauck L, Mehrhof F, Wegenka U, Cardoso M C, Dietz R. E2F-1 overexpression in cardiomyocytes induces downregulation of p21CIP1 and p27KIP1 and release of active cyclin-dependent kinases in the presence of insulin-like growth factor I.  Circ Res. 1999;  85 128-136
• 91 Kodama Y, Baxter R C, Martin J L. Insulin-like growth factor-I inhibits cell growth in the a549 non-small lung cancer cell line.  Am J Respir Cell Mol Biol. 2002;  27 336-344
• 92 Dupont J, Karas M, LeRoith D. The cyclin dependent kinase inhibitor p21CIP/WAF is a positive regulator of IGF-I-induced cell proliferation in MCF-7 human breast-cancer cells.  J Biol Chem. 2003;  278 37 256-37 264
• 93 Lai A, Sarcevic B, Prall O W, Sutherland R L. Insulin/insulin-like growth factor-I and estrogen cooperate to stimulate cyclin E-Cdk2 activation and cell Cycle progression in MCF-7 breast-cancer cells through differential regulation of cyclin E and p21(WAF1/Cip1).  J Biol Chem. 2001;  276 25 823-25 833
• 94 Cheng M, Olivier P, Diehl J A, Fero M, Roussel M F, Roberts J M, Sherr C J. The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts.  Embo J. 1999;  18 1571-1583
• 95 LaBaer J, Garrett M D, Stevenson L F, Slingerland J M, Sandhu C, Chou H S, Fattaey A, Harlow E. New functional activities for the p21 family of CDK inhibitors.  Genes Dev. 1997;  11 847-862
• 96 Weiss R H, Joo A, Randour C. p21(Waf1/Cip1) is an assembly factor required for platelet-derived growth factor-induced vascular smooth muscle cell proliferation.  J Biol Chem. 2000;  275 10 285-10 290
• 97 Bourcigaux N, Gaston V, Logie A, Bertagna X, Le Bouc Y, Gicquel C. High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors.  J Clin Endocrinol Metab. 2000;  85 322-330
• 98 Grandjean V, Smith J, Schofield P N, Ferguson-Smith A C. Increased IGF-II protein affects p57kip2 expression in vivo and in vitro: implications for Beckwith-Wiedemann syndrome.  Proc Natl Acad Sci USA. 2000;  97 5279-5284
• 99 Pardee A B. Gi events and regulation of cell proliferation.  Science. 1989;  246 603-608
• 100 Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T. Effect of a null mutation of the type I IGF receptor gene on growth and transformation of mouse embryo fibroblasts.  Mol Cell Biol. 1994;  14 3604-3612
• 101 Adesanya O O, Zhou J, Samathanam C, Powell-Braxton L, Bondy C A. Insulin-like growth factor 1 is required for G2 progression in the estradiol-induced mitotic cycle.  Proc Natl Acad Sci USA. 1999;  96 3287-3291
• 102 Morrione A, Valentinis B, Resnicoff M, Xu S, Baserga R. The role of mGrb10alpha in insulin-like growth factor I-mediated growth.  J Biol Chem. 1997;  272 26 382-26 387
• 103 Labbe J C, Picard A, Peaucellier G, Cavadore J C, Nurse P, Doree M. Purification of MPF from starfish: identification as the H1 histone kinase p34cdc2 and a possible mechanism for its periodic activation.  Cell. 1989;  57 253-263
• 104 Furlanetto R W, Harwell S E, Frick K K. Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro. .  Mol Endocrinol. 1994;  8 510-517
• 105 Surmacz E, Nugent P, Pietrzkowski Z, Baserga R. The role of the IGF1 receptor in the regulation of cdc2mRNA levels in fibroblasts.  Exp Cell Res. 1992;  199 275-278
• 106 Ellis M J, Leav B A, Yang Z, Rasmussen A, Pearce A, Zweibel J A, Lippman M E, Cullen K J. Affinity for the insulin-like growth factor-II (IGF-II) receptor inhibits autocrine IGF-II activity in MCF-7 breast-cancer cells.  Mol Endocrinol. 1996;  10 286-297
• 107 van der Burg B, Rutteman G R, Blankenstein M A, de Laat S W, van Zoelen E J. Mitogenic stimulation of human breast-cancer cells in a growth factor-defined medium: synergistic action of insulin and estrogen.  J Cell Physiol. 1988;  134 101-108
• 108 Stewart A J, Johnson M D, May F E, Westley B R. Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast-cancer cells.  J Biol Chem. 1990;  265 21 172-21 178
• 109 Lee A V, Jackson J G, Gooch J L, Hilsenbeck S G, Coronado-Heinsohn E, Osborne C K, Yee D. Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo.  Mol Endocrinol. 1999;  13 787-796
• 110 Hamelers I H, Steenbergh P H. Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells.  Endocr Relat Cancer. 2003;  10 331-345
• 111 Benassi M S, Molendini L, Gamberi G, Magagnoli G, Ragazzini P, Gobbi G A, Sangiorgi L, Pazzaglia L, Asp J, Brantsing C, Picci P. Involvement of INK4A gene products in the pathogenesis and development of human osteosarcoma.  Cancer. 2001;  92 3062-3067
• 112 Kanoe H, Nakayama T, Murakami H, Hosaka T, Yamamoto H, Nakashima Y, Tsuboyama T, Nakamura T, Sasaki M S, Toguchida J. Amplification of the CDK4 gene in sarcomas: tumor specificity and relationship with the RB gene mutation.  Anticancer Res. 1998;  18 2317-2321
• 113 Spirin K S, Simpson J F, Takeuchi S, Kawamata N, Miller C W, Koeffler H P. p27/Kip1 mutation found in breast cancer.  Cancer Res. 1996;  56 2400-2404
• 114 Lung J C, Chu J S, Yu J C, Yue C T, Lo Y L, Shen C Y, Wu C W. Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instability.  Genes Chromosomes Cancer. 2002;  34 276-284
• 115 An H X, Beckmann M W, Reifenberger G, Bender H G, Niederacher D. Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation.  Am J Pathol.. 1999;  154 113-118
• 116 Borg A, Zhang Q X, Alm P, Olsson H, Sellberg G. The retinoblastoma gene in breast cancer: allele loss is not correlated with loss of gene protein expression.  Cancer Res. 1992;  52 2991-2994
• 117 Guo S S, Wu X, Shimoide A T, Wong J, Sawicki M P. Anomalous overexpression of p27(Kip1) in sporadic pancreatic endocrine tumors.  J Surg Res. 2001;  96 284-288
• 118 Ebert M P, Hernberg S, Fei G, Sokolowski A, Schulz H U, Lippert H, Malfertheiner P. Induction and expression of cyclin D3 in human pancreatic cancer.  J Cancer Res Clin Oncol. 2001;  127 449-454
• 119 Gerdes B, Ramaswamy A, Ziegler A, Lang S A, Kersting M, Baumann R, Wild A, Moll R, Rothmund M, Bartsch D K. p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb.  Ann Surg. 2002;  235 51-59
• 120 Nitti D, Belluco C, Mammano E, Marchet A, Ambrosi A, Mencarelli R, Segato P, Lise M. Low level of p27(Kip1) protein expression in gastric adenocarcinoma is associated with disease progression and poor outcome.  J Surg Oncol. 2002;  81 167-175
• 121 Schneider-Stock R, Boltze C, Lasota J, Miettinen M, Peters B, Pross M, Roessner A, Gunther T. High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors.  J Clin Oncol. 2003;  21 1688-1697
• 122 Liang B, Wang S, Yang X, Ye Y, Yu Y, Cui Z. Expressions of cyclin E, cyclin dependent kinase 2 and p57(KIP2) in human gastric cancer.  Chin Med J (Engl). 2003;  116 20-23
• 123 Tahara E. Genetic alterations in human gastrointestinal cancers. The application to molecular diagnosis.  Cancer. 1995;  75 1410-1417
• 124 Chetty R. p27 Protein and cancers of the gastrointestinal tract and liver: an overview.  J Clin Gastroenterol. 2003;  37 23-27
• 125 Jin M, Piao Z, Kim N G, Park C, Shin E C, Park J H, Jung H J, Kim C G, Kim H. p16 is a major inactivation target in hepatocellular carcinoma.  Cancer. 2000;  89 60-68
• 126 Qin L X, Tang Z Y. The prognostic molecular markers in hepatocellular carcinoma.  World J Gastroenterol. 2002;  8 385-392
• 127 Fernandez P L, Hernandez L, Farre X, Campo E, Cardesa A. Alterations of cell cycle-regulatory genes in prostate cancer.  Pathobiology. 2002;  70 1-10
• 128 Payton M, Scully S, Chung G, Coats S. Deregulation of cyclin E2 expression and associated kinase activity in primary breast tumors.  Oncogene. 2002;  21 8529-8534
• 129 Bartkova J, Rajpert-de Meyts E, Skakkebaek N E, Bartek J. D-type cyclins in adult human testis and testicular cancer: relation to cell type, proliferation, differentiation, and malignancy.  J Pathol. 1999;  187 573-581
• 130 Fujita M, Enomoto T, Haba T, Nakashima R, Sasaki M, Yoshino K, Wada H, Buzard G S, Matsuzaki N, Wakasa K, Murata Y. Alteration of p16 and p15 genes in common epithelial ovarian tumors.  Int J Cancer. 1997;  74 148-155
• 131 Sasano H, Comerford J, Silverberg S G, Garrett C T. An analysis of abnormalities of the retinoblastoma gene in human ovarian and endometrial carcinoma.  Cancer. 1990;  66 2150-2154
• 132 Chakravarthy M V, Abraha T W, Schwartz R J, Fiorotto M L, Booth F W. Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3’-kinase/Akt signaling pathway.  J Biol Chem. 2000;  275 35 942 - 35 952
• 133 Takahashi Y, Tobe K, Kadowaki H, Katsumata D, Fukushima Y, Yazaki Y, Akanuma Y, Kadowaki T. Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts.  Endocrinology. 1997;  138 741-750
• 134 Kurihara S, Hakuno F, Takahashi S. Insulin-like growth factor-I-dependent signal transduction pathways leading to the induction of cell growth and differentiation of human neuroblastoma cell line SH-SY5Y: the roles of MAP kinase pathway and PI 3-kinase pathway.  Endocr J. 2000;  47 739-751
• 135 Talavera F, Bergman C, Pearl M L, Connor P, Roberts J A, Menon K M. cAMP and PMA enhance the effects of IGF-I in the proliferation of endometrial adenocarcinoma cell line HEC-1-A by acting at the G1 phase of the cell cycle.  Cell Prolif. 1995;  28 121-136
• 136 Yoshinouchi M, Baserga R. The role of the IGF-I receptor in the stimulation of cells by short pulses of growth factors.  Cell Prolif. 1993;  26 139-146
• 137 Krystal G W, Sulanke G, Litz J. Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy.  Mol Cancer Ther. 2002;  1 913-922
• 138 Satyamoorthy K, Li G, Vaidya B, Patel D, Herlyn M. Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways.  Cancer Res. 2001;  61 7318-7324
• 139 El-Badry O M, Helman L J, Chatten J, Steinberg S M, Evans A E, Israel M A. Insulin-like growth factor II-mediated proliferation of human neuroblastoma.  J Clin Invest. 1991;  87 648-657