Abstract
Transformation of normal melanocytes to metastatic melanoma cells is characterized by loss of dependency on external growth factors required for the viability and proliferation of normal melanocytes. The molecular events that lead to melanoma cell autonomous growth are not well defined, but are likely to include sustained activity of cyclin-dependent kinases (CDK2, CDK4 and CDK6) as a result of loss of CDK inhibitors (such as p16INK4a and possibly p27KIP1), and persistent upregulation of several cyclins (cyclin D1, cyclin A and cyclin E), the positive regulators of CDKs. CDKs phosphorylate, and consequently, inactivate the retinoblastoma family of tumor suppressor proteins (pRb, p107 and p130), termed pocket proteins. The inactivation of pocket proteins liberates E2F transcription factors from suppressive complexes ('free' E2F) that, in turn, induces the continuous expression of target genes whose products promote cell cycle progression. In normal melanocytes, external growth factors suppress the activity of all three pocket proteins, allowing E2F activity to accumulate and sustain transcription of target genes required for cell proliferation. In contrast, in melanoma cells from advanced lesions, all three pocket proteins are highly phosphorylated and inactive, even in the absence of environmental mitogens, and free E2F activity is constitutively high. Manipulations of normal mouse melanocytes in vitro, and in vivo in transgenic mouse expressing ectopic genes, further support the notion that growth rate, and release from dependency on external mitogens, positively correlate with inactivation of pocket proteins. The latter has been accomplished by sustained cell surface receptor stimulation, such as constitutive high expression of a growth factor, or by sequestration with dominantly acting viral proteins. Taken together, chronic hyperphosphorlyation/inactivation of pRb, p107 and p130 is probably one of the key events in converting growth-factor dependent normal melanocytes, to autonomously growing melanoma cells. Since all pocket proteins are regulated by CDKs activity, it is likely that agents that inhibit this class of enzymes will be effective in treating melanoma patients.
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References
Pawson T, Hunter T: Signal transduction and growth control in normal and cancer cells (editorial) (Review). Curr Opin Genet Dev 4: 1-4, 1994
Sherr CJ: Cancer cell cycles. Science 274: 1672-1677, 1996
Porter AC, Vaillancourt RR: Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene 17: 1343-1352, 1998
Böhm M, Moellmann G, Cheng E, Alvarez-Franco M, Wagner S, Sassone-Corsi P, Halaban R: Identification of p90RSK as the probable CREB-Ser133 kinase in human melanocytes. Cell Growth Differ 6: 291-302, 1995
Halaban R: Growth regulation in normal and malignant melanocytes. In: Hecker E, Marks F, Jung EG, Tilgen W (eds), Recent Results in Cancer Research, Vol 128, Springer-Verlag, Berlin-Heidelberg, 1993, pp 133-149
Halaban R, Rubin JS, Funasaka Y, Cobb M, Boulton T, Faletto D, Rosen E, Chan A, YoKo K, White W, Cook C, Moellmann G: Met and hepatocyte growth factor/scatter factor signal transduction in normal melanocytes and melanoma cells. Oncogene 7: 2195-2206, 1992
Funasaka Y, Boulton T, Cobb M, Yarden Y, Fan B, Lyman SD, Williams DE, Anderson DM, Zakut R, Mishima Y, Halaban R: c-Kit kinase induces a cascade of protein tyrosine-phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down regulated in melanomas. Mol Biol Cell 3: 197-209, 1992
Imokawa G, Yada Y, Miyagishi M: Endothelins secreted from human keratinocytes are intrinsic mitogens for human melanocytes. J Biol Chem 267: 24675-24680, 1992
Abdel-Malek Z, Swope VB, Suzuki I, Akcali C, Harriger MD, Boyce ST, Urabe K, Hearing VJ: Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. Proc Natl Acad Sci USA 92: 1789-1793, 1995
Hunt G, Todd C, Cresswell JE, Thody AJ: Alpha-melanocyte stimulating hormone and its analogue Nle4DPhe7 alpha-MSH affect morphology, tyrosinase activity and melanogenesis in cultured human melanocytes. J Cell Sci 107: 205-211, 1994
Suzuki I, Cone RD, Im S, Nordlund J, Abdel-Malek ZA: Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. Endocrinology 137: 1627-1633, 1996
Swope VB, Medrano EE, Smalara D, Abdel-Malek ZA: Long-term proliferation of human melanocytes is supported by the physiologic mitogens alpha-melanotropin, endothelin-1, and basic fibroblast growth factor. Exp Cell Res 217: 453-459, 1995
Matsumoto K, Tajima H, Nakamura T: Hepatocyte growth factor is a potent stimulator of human melanocyte DNA synthesis and growth. Biochem Biophys Res Commun 176: 45-51, 1991
Halaban R: Growth factors and melanomas (Review). Sem Oncol 23: 673-681, 1996
Bull HA, Bunker CB, Terenghi G, Springall DR, Zhao Y, Polak JM, Dowd PM: Endothelin-1 in human skin: immunolocalization, receptor binding, mRNA expression, and effects on cutaneous microvascular endothelial cells. J Invest Dermatol 97: 618-623, 1991
Hara M, Yaar M, Gilchrest BA: Endothelin-1 of keratinocyte origin is a mediator of melanocyte dendricity. J Invest Dermatol 105: 744-748, 1995
Halaban R, Tyrrell L, Longley J, Yarden Y, Rubin J: Pigmentation and proliferation of human melanocytes and the effects of melanocyte-stimulating hormone and ultraviolet B light. Ann NY Acad Sci 680: 290-301, 1993
Tada A, Suzuki I, Im S, Davis MB, Cornelius J, Babcock G, Nordlund JJ, Abdel-Malek ZA: Endothelin-1 is a paracrine growth factor that modulates melanogenesis of human melanocytes and participates in their responses to ultraviolet radiation. Cell Growth Differ 9: 575-584, 1998
Pawelek JM, Chakraborty AK, Osber MP, Orlow SJ, Min KK, Rosenzweig KE, Bolognia JL: Molecular cascases in UV-induced melanogenesis: a central role for melanotropins? (Review). Pigm Cell Res 5: 348-356, 1992
Bhardwaj RS, Luger TA: Proopiomelanocortin production by epidermal cells: evidence for an immune neuroendocrine network in the epidermis (Review). Arch Dermatol Res 287: 85-90, 1994
Luger TA, Scholzen T, Brzoska T, Becher E, Slominski A, Paus R: Cutaneous immunomodulation and coordination of skin stress responses by alpha-melanocyte-stimulating hormone. Ann NY Acad Sci 840: 381-394, 1998
Luger TA: Immunomodulation by UV light: role of neuropeptides. Eur J Dermatol 8: 198-199, 1998
Costa JJ, Demetri GD, Harrist TJ, Dvorak AM, Hayes DF, Merica EA, Menchaca DM, Gringeri AJ, Schwartz LB, Galli SJ: Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J Exp Med 183: 2681-2686, 1996
Grichnik JM, Burch JA, Burchette J, Shea CR: The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol 111: 233-238, 1998
Lerner AB, McGuire J: Effect of α-and β-melanocyte-stimulating hormones on the skin colour of man. Nature 189: 176-179, 1961
Hadley ME, Sharma SD, Hruby VJ, Levine N, Dorr RT: Melanotropic peptides for therapeutic and cosmetic tanning of the skin (Review). Ann NY Acad Sci 680:424-439, 1993
Hadley ME, Hruby VJ, Blanchard J, Dorr RT, Levine N, Dawson BV, al-Obeidi F, Sawyer TK: Discovery and development of novel melanogenic drugs. Melanotan-I and-II. Pharm Biotechnol 11: 575-595, 1998
Halaban R, Moellmann G: White mutants in mice shedding light on humans. J Invest Dermatol 100(Suppl): 176s-185s, 1993
Spritz RA: Molecular basis of human piebaldism (Review). J Invest Dermatol 103: 137S-140S, 1994
Puffenberger EG, Hosoda K, Washington SS, Nakao K, Dewit D, Yanagisawa M, Chakravarti A: A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 79: 1257-1266, 1994
Artie T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, Munnich A, Lyonnet S: Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet 4: 2407-2409, 1995
Edery P, Attie T, Amiel J, Pelet A, Eng C, Hofstra RM, Martelli H, Bidaud C, Munnich A, Lyonnet S: Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 12: 442-444, 1996
Amiel J, Attie T, Jan D, Pelet A, Edery P, Bidaud C, Lacombe D, Tam P, Simeoni J, Flori E, Nihoul-Fekete C, Munnich A, Lyonnet S: Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet 5: 355-357, 1996
Seri M, Yin L, Barone V, Bolino A, Celli I, Bocciardi R, Pasini B, Ceccherini I, Lerone M, Kristoffersson U, Larsson LT, Casasa JM, Cass DT, Abramowicz MJ, Vanderwinden JM, Kravcenkiene I, Baric I, Silengo M, Martucciello G, Romeo G: Frequency of RET mutations in long-and short-segment Hirschsprung disease. Hum Mutat 9: 243-249, 1997
Hofstra RM, Osinga J, Tan-Sindhunata G, Wu Y, Kamsteeg EJ, Stulp RP, van Ravenswaaij-Arts C, Majoor-Krakauer D, Angrist M, Chakravarti A, Meijers C, Buys CH: A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat Genet 12: 445-447, 1996
Fleischman RA: From white spots to stem cells: the role of the Kit receptor in mammalian development (Review). Trends Genet 9: 285-290, 1993
Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, Yanagisawa M: Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79: 1277-1285, 1994
Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung JC, Giaid A, Yanagisawa M: Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79: 1267-1276, 1994
Pawson T: Protein modules and signalling networks. Nature 373: 573-580, 1995
Adams PD, Kaelin WG, Jr: Transcriptional Control by E2F (Review). Semin Cancer Biol 6: 99-108, 1995
Adams PD, Kaelin WG, Jr: The cellular effects of E2F over-expression (Review). Curr Top Microbiol Immunol 208: 79-93, 1996
Sherr CJ: Growth factor-regulated Gl cyclins (Review). Stem Cells 1: 47-55, 1994
Sherr CJ: G1 phase progression: cycling on cue (see comments) (Review). Cell 79: 551-555, 1994
Weinberg RA: The retinoblastoma protein and cell cycle control (Review). Cell 81: 323-330, 1995
Kaelin WG, Jr: Recent insights into the functions of the retinoblastoma susceptibility gene product (Review) (183 refs.). Cancer Invest 15: 243-254, 1997
Sherr CJ: Mammalian G1 cyclins and cell cycle progression (Review). Proc Assoc Am Physicians 107: 181-186, 1995
Zarkowska T, Mittnacht S: Differential phosphorylation of the retinoblastoma protein by G1/S cyclin-dependent kinases. J Biol Chem 272: 12738-12746, 1997
Weinberg RA: The molecular basis of carcinogenesis — understanding the cell cycle clock. Cytokines Mol Ther 2: 105-110, 1996
Taya Y: Rb kinases and Rb-binding proteins: new points of view (Review). Trends Biochem Sci 22: 14-17, 1997
Pardee A: G1 events and regulation of cell proliferation. Science 246: 603-608, 1989
Bartek J, Bartkova J, Lukas J: The retinoblastoma protein pathway and the restriction point. Curr Opin Cell Biol 8: 805-814, 1996
Planas-Silva MD, Weinberg RA: The restriction point and control of cell proliferation (Review article). Curr Opin Cell Biol 9: 768-772, 1997
Nevins JR: Toward an understanding of the functional complexity of the E2F and retinoblastoma families (Review) (100 refs.). Cell Growth Differ 9: 585-593, 1998
Jacks T, Weinberg RA: Cell-cycle control and its watchman. Nature 381: 643-644, 1996
Weinberg RA: How cancer arises (Review) (0 refs.). Sci Am 275: 62-70, 1996
Grana X, Garriga J, Mayol X: Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth. Oncogene 17: 3365-3383, 1998
Johnson DG, Schneider-Broussard R: Role of E2F in cell cycle control and cancer. Front Biosci 27: d447-d448, 1998
Hiyama H, Iavarone A, Reeves SA: Regulation of the CDK inhibitor p21 gene during cell cycle progression is under the control of the transcription factor E2F. Oncogene 16: 1513-1523, 1998
Kos L, Aronzon A, Takayama H, Maina F, Ponzetto C, Merlino G, Pavan W: Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development. Pigm Cell Res 12: 13-21, 1999
Otsuka T, Takayama H, Sharp R, Celli G, LaRochelle WJ, Bottaro DP, Ellmore N, Vieira W, Owens JW, Anver M, Merlino G: c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. Cancer Res 58: 5157-5167, 1998
Kato M, Takahashi M, Akhand AA, Liu W, Dai Y, Shimizu S, Iwamoto T, Suzuki H, Nakashima I: Transgenic mouse model for skin malignant melanoma. Oncogene 17: 1885-1888, 1998
Anders F: Tumour formation in platyfish-swordtail hybrids as a problem of gene regulation. Experientia 23: 1-10, 1967
Schartl A, Malitschek B, Kazianis S, Borowsky R, Schartl M: Spontaneous melanoma formation in nonhybrid Xiphophorus. Cancer Res 55: 159-165, 1995
Wellbrock C, Fischer P, Schartl M: Receptor tyrosine kinase Xmrk mediates proliferation in Xiphophorus melanoma cells. Int J Cancer 76: 437-442, 1998
Wellbrock C, Geissinger E, Gomez A, Fischer P, Friedrich K, Schartl M: Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma. Oncogene 16: 3047-3056, 1998
Powell MB, Hyman P, Bell OD, Balmain A, Brown K, Alberts D, Bowden GT: Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 Ha-ras gene regulated by a mouse tyrosinase promoter. Molec Carcinogen 12: 82-90, 1995
Chin L, Pomerantz J, Polsky D, Jacobson M, Cohen C, Cordon-Cardo C, Horner II JW, DePinho RA: Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev 11: 2822-2834, 1997
Chin L, Pomerantz J, Wwong M, Holash J, Bardeesy N, Shen Q, O'hagan R, Pantginis J, Zhou H, Horner II JW, Cordon-Cardo C, Yancopoulos GD, DePinho RA: Essential role for oncogenic Ras in tumour maintenance. Nature 400: 468-472, 1999
Sherr CJ: Mammalian G1 cyclins (Review). Cell 73: 1059-1065, 1993
Kerhoff E, Rapp UR: Cell cycle targets of Ras/Raf signalling. Oncogene 17: 1457-1462, 1998
Larue L, Dougherty N, Mintz B: Genetic predisposition of transgenic mouse melanocytes to melanoma results in malignant melanoma after exposure to a low ultraviolet B intensity nontumorigenic for normal melanocytes. Proc Natl Acad Sci USA 89: 9534-9538, 1992
Mintz B, Silvers WK: Transgenic mouse model of malignant skin melanoma. Proc Natl Acad Sci USA 90: 8817-8821, 1993
Klein-Szanto AJ, Silvers WK, Mintz B: Ultraviolet radiation-induced malignant skin melanoma in melanoma-susceptible transgenic mice. Cancer Res 54: 4560-4572, 1994
Kelsall SR, Mintz B: Metastatic cutaneous melanoma promoted by ultraviolet radiation in mice with transgene-initiated low melanoma susceptibility. Cancer Res 58: 4061-4065, 1998
Wilson RE, Dooley TP, Hart IR: Induction of tumorigenicity and lack of in vitro growth requirement for 12-O-tetradecancoylphorbol-13-acetate by transfection of murine melanocytes with v-Ha-ras. Cancer Res 49: 711-716, 1989
Dotto GP, Moellmann G, Ghosh S, Edwards M, Halaban R: Transformation of murine melanocytes by basic fibroblast growth factor cDNA and oncogenes and selective suppression of the transformed phenotype in a reconstituted cutaneous environment. J Cell Biol 109: 3115-3128, 1989
Ramon Y, Cajal S, Suster S, Halaban R, Filvaroff E, Dotto GP: Induction of different morphologic features of malignant melanoma and pigmented lesions after transformation of murine melanocytes with bFGF-cDNA and H-ras, myc, neu, and E1a oncogenes. Am J Pathol 138: 349-358, 1991
Halaban R, Böhm M, Dotto P, Moellmann G, Cheng E, Zhang YH: Growth regulatory proteins that repress differentiation markers in melanocytes also downregulate the transcription factor Microphthalmia. J Invest Dermatol 106: 1266-1272, 1996
Dooley TP, Wilson RE, Jones NC, Hart IR: Polyoma middle T abrogates TPA requirement of murine melanocytes and induces malignant melanoma. Oncogene 3: 531-535, 1988
Albino AP, Sozzi G, Nanus DM, Jhanwar SC, Houghton AN: Malignant transformation of human melanocytes: induction of a complete melanoma phenotype and genotype. Oncogene 7: 2315-2321, 1992
Jambrosic J, Mancianti ML, Ricciardi R, Sela BA, Koprowski H, Herlyn M: Transformation of normal human melanocytes and non-malignant nevus cells by adenovirus 12-SV40 hybrid virus. Int J Cancer 44: 1117-1123, 1989
Herlyn M, Satyamoorthy K: Activated ras. Yet another player in melanoma? (comment) (Review). Am J Pathol 149: 739-744, 1996
Edery P, Eng C, Munnich A, Lyonnet S: RET in human development and oncogenesis. Bioessays 19: 389-395, 1997
Natali PG, Nicotra MR, Di Renzo MF, Prat M, Bigotti A, Cavaliere R, Comoglio PM: Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression. Br J Cancer 68: 746-750, 1993
Halaban R, Rubin W, White W: Met and HGF/SF in normal melanocytes and melanoma cells. In: Goldberg ID (ed) Hepatocyte Growth Factor-Scatter Factor and the c-Met Receptor, Birkhäuser Verlag, Basel, Switzerland, 1993, pp 329-339
Kraehn GM, Schartl M, Peter RU: Human malignant melanoma-a genetic disease. Cancer 75: 1228-1237, 1995
Natali PG, Nicotra MR, Digiesi G, Cavaliere R, Bigotti A, Trizio D, Segatto O: Expression of gp185HER-2 in human cutaneous melanoma: implications for experimental immunotherapeutics. Int J Cancer 56: 341-346, 1994
Luan J, Shattuck-Brandt R, Haghnegahdar H, Owen JD, Strieter R, Burdick M, Nirodi C, Beauchamp D, Johnson KN, Richmond A: Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression. J Leukoc Biol 62: 588-597, 1997
Rodeck U, Herlyn M: Growth factors in melanoma (Review). Cancer Metastasis Rev 10: 89-101, 1991
Richmond A: The pathogenic role of growth factors in melanoma (Review). Semin Dermatol 10: 246-255, 1991
Richmond A, Thomas HG: Purification of melanoma growth stimulatory activity. J Cell Physiol 129: 375-384, 1986
Bordoni R, Fine R, Murray D, Richmond A: Characterization of the role of melanoma growth stimulatory activity (MGSA) in the growth of normal melanocytes, nevocytes, and malignant melanocytes. J Cell Biochem 44: 207-219, 1990
Balentien E, Mufson BE, Shattuck RL, Derynck R, Richmond A: Effects of MGSA/GRO alpha on melanocyte transformation. Oncogene 6: 1115-1124, 1991
Rodeck R, Melber K, Kath R, Menssen H-D, Varello M, Atkinson B, Herlyn M: Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes. J Invest Dermatol 97: 20-26, 1991
Rodeck U, Becker D, Herlyn M: Basic fibroblast growth factor in human melanoma (Review). Cancer Cells 3: 308-311, 1991
Albino AP: The role of oncogenes and growth factors in progressive melanomagenesis (Review). Pigm Cell Res 2: 199-218, 1992
Scott G, Stoler M, Sarkar S, Halaban R: Localization of basic fibroblast growth factor mRNA in melanocytic lesions by in situ hybridization. J Invest Dermatol 96: 318-322, 1991
Ueda M, Funasaka Y, Ichihashi M, Mishima Y: Stable and strong expression of basic fibroblast growth factor in naevus cell naevus contrasts with aberrant expression in melanoma. Br J Dermatol 130: 320-324, 1994
al-Alousi S, Carlson JA, Blessing K, Cook M, Karaoli T, Barnhill RL: Expression of basic fibroblast growth factor in desmoplastic melanoma. J Cutan Pathol 23: 118-125, 1996
Reed JA, McNutt NS, Albino AP: Differential expression of basic fibroblast growth factor (bFGF) in melanocytic lesions demonstrated by in situ hybridization. Implications for tumor progression. Am J Pathol 144: 329-336, 1994
Xerri L, Battyani Z, Grob JJ, Parc P, Hassoun J, Bonerandi JJ, Birnbaum D: Expression of FGF1 and FGFR1 in human melanoma tissues. Melanoma Res 6: 223-230, 1996
Yayon A, Ma YS, Safran M, Klagsbrun M, Halaban R: Suppression of autrocrine cell proliferation and tumorigenesis of human melanoma cells and fibroblast growth factor transformed fibroblasts by a kinase-deficient FGF receptor 1: evidence for the involvement of Src-family kinases. Oncogene 14: 2999-3009, 1997
Wang Y, Becker D: Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nature Med 3: 887-893, 1997
Dyson N, Bernards R, Friend SH, Gooding LR, Hassell JA, Major EO, Pipas JM, Vandyke T, Harlow E: Large T antigens of many polyomaviruses are able to form complexes with the retinoblastoma protein. J Virol 64: 1353-1356, 1990
Stubdal H, Zalvide J, DeCaprio JA: Simian virus 40 large T antigen alters the phosphorylation state of the Rb-related proteins p130 and p107. J Virol 70: 2781-2788, 1996
Stubdal H, Zalvide J, Campbell KS, Schweitzer C, Roberts TM, DeCaprio JA: Inactivation of pRB-related proteins p130 and p107 mediated by the J domain of simian virus 40 large T antigen. Mol Cell Biol 17: 4979-4990, 1997
Zalvide J, Stubdal H, DeCaprio JA: The J domain of simian virus 40 large T antigen is required to functionally inactivate RB family proteins. Mol Cell Biol 18: 1408-1415, 1998
Ranade K, Hussussian CJ, Sikorski RS, Varmus HE, Goldstein AM, Tucker MA, Serrano M, Hannot GJ, Beach D, Dracopoli NC: Mutations associated with familial melanoma impair p16INK4 function (letter). Nat Genet 10: 114-116, 1995
Liu L, Lassam NJ, Slingerland JM, Bailey D, Cole D, Jenkins R, Hogg D: Germline p16INK4a mutation and protein dysfunction in a family with inherited melanoma. Oncogene 11: 405-412, 1995
Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC: Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12: 97-99, 1996
Walker GJ, Hussussian CJ, Flores JF, Glendening JM, Haluska FG, Dracopoli NC, Hayward NK, Fountain JW: Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum Mol Genet 4: 1845-1852, 1995
Haluska FG, Housman DE: Recent advances in the molecular genetics of malignant melanoma. Cancer Surv 25: 277-292, 1995
Cannon-Albright LA, Kamb A, Skolnick M: A review of inherited predisposition to melanoma. (Review)(66 refs.). Semin Oncol 23: 667-672, 1996
Kamb A: Cyclin-dependent kinase inhibitors and human cancer (Review) (44 refs.). Curr Topics Microbiol Immunol 227: 139-148, 1998
Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J, Bartek J: The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res 56: 5475-5483, 1996
Halaban R, Miglarese MR, Smicun Y, Puig S: Melanomas, from the cell cycle point of view (Review). Int J Mol Med 1: 419-425, 1998
Horowitz JM, Park S-H, Bogenman E, Cheng J-C, Yandell DW, Kaye FJ, Minna JD, Dryja TP, Weinberg RA: Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 87: 2772-2779, 1990
Bataille V, Hiles R, Bishop JA: Retinoblastoma, melanoma and the atypical mole syndrome. Br J Dermatol 132: 134-138, 1995
Moll AC, Imhof SM, Bouter LM, Tan KE: Second primary tumors in patients with retinoblastoma. A review of the literature (Review) (33 refs.). Ophthalmic Genet 18: 27-34, 1997
Kowalik TF, DeGregori J, Schwarz JK, Nevins JR: E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol 69: 2491-2500, 1995
Phillips AC, Bates S, Ryan KM, Helin K, Vousden KH: Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev 11: 1853-1863, 1997
Holmberg C, Helin K, Sehested M, Karlstrom O: E2F-1-induced p53-independent apoptosis in transgenic mice. Oncogene 17: 143-155, 1998
DeGregori J, Leone G, Miron A, Jakoi L, Nevins JR: Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci USA 94: 7245-7250, 1997
Shan B, Farmer AA, Lee WH: The molecular basis of E2F-1/DP-1-induced S-phase entry and apoptosis. Cell Growth Differ 7: 689-697, 1996
Ohta Y, Kijima H, Kashanisabet M, Scanlon KJ: Suppression of the malignant phenotype of melanoma cells by anti-oncogene ribozymes. J Invest Dermatol 106: 275-280, 1996
Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA: Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368: 753-756, 1994
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RSr, Johnson BE, Skolnick MH: A cellcycle regulator potentially involved in genesis of many tumor types (see comments). Science 264: 436-440, 1994
Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Feldhaus J et al.: Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 8: 23-26, 1994
Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmannhieb E, Deplaen E, Hankeln T, Zumbuschenfelde KHM, Beach D: A p 16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269: 1281-1284, 1995
Halaban R, Cheng E, Zhang Y, Mandigo CE, Miglarese MR: Release of cell cycle constraints in mouse melanocytes by overexpressed mutant E2F1E132, but not by deletion of p16INK4A or p21WAF1/CIP1. Oncogene 16: 2489-2501, 1998
Castellano M, Gabrielli BG, Hussussian CJ, Dracopoli NC, Hayward NK: Restoration of CDKN2A into melanoma cells induces morphologic changes and reduction in growth rate but not anchorage-independent growth reversal. J Invest Dermatol 109: 61-68, 1997
Florenes VA, Lu C, Bhattacharya N, Rak J, Sheehan C, Slingerland JM, Kerbel RS: Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. Oncogene 18: 1023-1032, 1999
Jiang HP, Lin JJ, Su ZZ, Goldstein NI, Fisher PB: Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 11: 2477-2486, 1995
Trotter MJ, Tang L, Tron VA: Overexpression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in human cutaneous malignant melanoma. J Cutan Pathol 24: 265-271, 1997
Macleod KF, Sherry N, Hannon G, Beach D, Tokino T, Kinzler K, Vogelstein B, Jacks T: p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage Genes Dev 9: 935-944, 1995
Mantel C, Luo Z, Canfield J, Braun S, Deng C, Broxmeyer HE: Involvement of p21cip-1 and p27kip-1 in the molecular mechanisms of steel factor-induced proliferative synergy in vitro and of p21cip-1 in the maintenance of stem/progenitor cells in vivo. Blood 88: 3710-3719, 1996
Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ: The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 18: 1571-1583, 1999
Halaban R, Funasaka Y, Lee P, Rubin J, Ron D, Birnbaum D: Fibroblast growth factors in normal and malignant melanocytes. Ann NY Acad Sci 638: 232-243, 1991
Gaudray P, Szepetowski P, Escot C, Birnbaum D, Theillet C: DNA amplification at 11q13 in human cancer: from complexity to perplexity (Review). Mutat Res 276: 317-328, 1992
Sherr CJ: D-type cyclins (Review). Trends Biochem Sci 20: 187-190, 1995
Bartkova J, Lukas J, Strauss M, Bartek J: Cyclin D1 oncoprotein aberrantly accumulates in malignancies of diverse histogenesis. Oncogene 10: 775-778, 1995
Hall M, Peters G: Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer (Review) (219 refs.). Adv Cancer Res 68: 67-108, 1996
Lukas J, Herzinger T, Hansen K, Moroni MC, Resnitzky D, Helin K, Reed SI, Bartek J: Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes Dev 11: 1479-1492, 1997
Gray-Bablin J, Zalvide J, Fox MP, Knickerbocker CJ, DeCaprio JA, Keyomarsi K: Cyclin E, a redundant cyclin in breast cancer. Proc Natl Acad Sci USA 93: 15215-15220, 1996
Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ: Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res 56: 2973-2978, 1996
Patel V, Senderowicz AM, Pinto D, Jr, Igishi T, Raffeld M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS: Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J Clin Invest 102: 1674-1681, 1998
Schrump DS, Matthews W, Chen GA, Mixon A, Altorki NK: Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. Clin Cancer Res 4: 2885-2890, 1998
Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, Hill K, Steinberg SM, Figg WD, Tompkins A, Arbuck SG, Sausville EA: Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol 16: 2986-2999, 1998
Halaban R, Cheng C, Smicun Y, Germino J: Deregulated E2F transcriptional activity in autonomously growing melanoma cells. J Exp Med, in press, 2000
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Halaban, R. Melanoma Cell Autonomous Growth: The Rb/E2F Pathway. Cancer Metastasis Rev 18, 333–343 (1999). https://doi.org/10.1023/A:1006396104073
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DOI: https://doi.org/10.1023/A:1006396104073