FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2057394091> ?p ?o ?g. }

• W2057394091 endingPage "792" @default.
• W2057394091 startingPage "783" @default.
• W2057394091 abstract "Because of subtle differences between mouse and human skin, mice have traditionally not been an ideal model to study melanoma development. Understanding of the molecular mechanisms of melanoma predisposition, however, has been greatly improved by modeling various pathway defects in the mouse. This review analyzes the latest developments in mouse models of melanoma, and summarizes what these may indicate about the development of this neoplasm in humans. Mutations of genes involved in human melanoma have been recapitulated with some unexpected results, particularly with respect to the role of the two transcripts (Ink4a and Arf) encoded by the Cdkn2a locus. Both the Ink4a/pRb and Arf/p53 pathways are involved in melanoma development in mice, and possible mechanisms of cross-talk between the two pathways are discussed. We also know from mouse models that Ras/mitogen-activated protein kinase pathway activation is very important in melanoma development, either through direct activation of Ras (e.g., Hras G12V), or via activation of Ras-effector pathways by other oncogenes (e.g., Ret, Hgf/Sf). Ras can cooperate with the Arf/p53 pathway, and probably the Ink4a/Rb pathway, to induce melanoma. These three growth regulation pathways (Ink4a/pRb, Arf/p53, and Ras/mitogen-activated protein kinase) seem to represent three major “axes” of melanoma development in mice. Finally, we summarize experiments using genetically modified mice that have given indications of the intensity and timing of ultraviolet radiation exposure that may be most responsible for melanoma development. Because of subtle differences between mouse and human skin, mice have traditionally not been an ideal model to study melanoma development. Understanding of the molecular mechanisms of melanoma predisposition, however, has been greatly improved by modeling various pathway defects in the mouse. This review analyzes the latest developments in mouse models of melanoma, and summarizes what these may indicate about the development of this neoplasm in humans. Mutations of genes involved in human melanoma have been recapitulated with some unexpected results, particularly with respect to the role of the two transcripts (Ink4a and Arf) encoded by the Cdkn2a locus. Both the Ink4a/pRb and Arf/p53 pathways are involved in melanoma development in mice, and possible mechanisms of cross-talk between the two pathways are discussed. We also know from mouse models that Ras/mitogen-activated protein kinase pathway activation is very important in melanoma development, either through direct activation of Ras (e.g., Hras G12V), or via activation of Ras-effector pathways by other oncogenes (e.g., Ret, Hgf/Sf). Ras can cooperate with the Arf/p53 pathway, and probably the Ink4a/Rb pathway, to induce melanoma. These three growth regulation pathways (Ink4a/pRb, Arf/p53, and Ras/mitogen-activated protein kinase) seem to represent three major “axes” of melanoma development in mice. Finally, we summarize experiments using genetically modified mice that have given indications of the intensity and timing of ultraviolet radiation exposure that may be most responsible for melanoma development. retinal pigment epithelium 7,12-dimethylbenz[a]anthracene tumor suppressor gene protein tyrosine kinase cyclin-dependent kinase ocular melanomas cutaneous melanomas receptor tyrosine kinase Historically, the mouse has not been a good model for studying melanoma. Advances in methodologies to generate transgenic and knockout animals, however, have enabled researchers to assess the in vivo effects of pathways thought to be dysregulated in human melanoma development. Furthermore, new experimental ultraviolet radiation (UVR) treatment regimens have shed some light on the environmental events thought to contribute to the genesis of this neoplasm. Melanoma is a tumor of pigment-producing cells (melanocytes) that differentiate from neural crest progenitor cells during embryonic development. Melanocytes are located in the skin, hair follicles, stria vascularis of the inner ear, and uveal tract of the eye. Ocular (uveal) melanomas arise from neural crest derived melanocytes within the eye. The only pigment cells not arising from neural crest precursors are those of the retinal pigment epithelium (RPE), which are derived from epithelial cells in the optic cup. During embryonic development neural crest cells differentiate within the embryo through two major pathways: (i) the “ventral” pathway, which gives rise to neurons and glial cells of the peripheral nervous system, and (ii) the “dorsolateral” pathway from which pigment cells arise. Pigment cell precursors (melanoblasts) migrate first to the dermis and differentiate (possibly under the influence of α-melanocyte-stimulating hormone and other factors), then to the epidermis (Quevedo and Fleischmann, 1980Quevedo W. Fleischmann R. Developmental biology of mammalian melanocytes.J Invest Dermatol. 1980; 75: 116-120Crossref PubMed Scopus (50) Google Scholar). In contrast to humans, in which there is a strong association between UV exposure and melanoma development (Whiteman et al., 2001Whiteman D. Whiteman C. Green A. Childhood sun exposure as a risk factor for melanoma. A systematic review of epidemiological studies.Cancer Causes Control. 2001; 12: 69-82Crossref PubMed Scopus (506) Google Scholar), normal adult mice do not develop melanomas, even after chronic exposure to UVR. Traditionally, shaved or hairless mice have been exposed to various acute (intense, short-term) and chronic (low level, long-term) UV treatments to simulate human sun exposure. These treatments promote various types of skin cancers, including squamous cell carcinoma, papilloma, and fibrosarcoma, but not melanoma (Gallagher et al., 1984Gallagher C. Canfield P. Greenhoak G. Reeve V. Characterization and histogenesis of tumors in the hairless mouse produced by low-dosage incremental ultraviolet radiation.J Invest Dermatol. 1984; 83: 169-174Crossref PubMed Scopus (76) Google Scholar). Even cotreatment with carcinogens such as 7,12-dimethylbenz[a]anthracene (DMBA) promote little or no melanoma development, although there is a significant increase in the frequency of the other skin cancers. The architecture of mouse and human skin shows some subtle differences, and it is thought that differences in melanocyte structure and location within the skin may be responsible for the inability to induce melanomas in mice with UVR. Epidermal melanocyte numbers increase substantially after birth for about 2 wk; however, in mouse skin, but not human skin, nonfollicular melanocyte numbers decline as they follow the basement membrane in the invagination process involved in the formation of hair follicles (Hirobe, 1995Hirobe T. Structure and function of melanocytes: Microscopic morphology and cell biology of mouse melanocytes in the epidermis and hair follicle.Histol Histopathol. 1995; 10: 223-237PubMed Google Scholar). Thus in adult mice most melanocytes are located in hair follicles (Hirobe, 1995Hirobe T. Structure and function of melanocytes: Microscopic morphology and cell biology of mouse melanocytes in the epidermis and hair follicle.Histol Histopathol. 1995; 10: 223-237PubMed Google Scholar), although some are still located in the epidermis, particularly in nonhairy skin (e.g., ears, footpads). It is thought that due to their location, follicular melanocytes may be more protected from UVR, although this has not been proven. A number of genetic abnormalities involved in human melanoma susceptibility and tumor progression have been recapitulated in mice. The purpose of this review is to outline the latest developments in mouse models of melanoma, and to summarize what these may indicate about the development of this neoplasm in humans. To begin, genes known to be involved in the development of human melanoma will be discussed, followed by a summary of each of the mouse models of melanoma generated to date. Lastly, the role of UVR in melanoma genesis in these animals will be critically assessed. The hallmark of solid tumor development is the acquisition of multiple genetic defects involving the inactivation of tumor suppressor genes (TSG) and the activation of oncogenes. In cutaneous melanoma, nonrandom deletions and rearrangements are seen in several chromosomal regions, including 1p, 7q, 9p, 10q, and 11q (Dracopoli and Fountain, 1996Dracopoli N.C. Fountain J.W. CDKN2A mutations in melanoma.Cancer Surveys. 1996; 26: 115-132PubMed Google Scholar). At present, the two most important TSG involved in human melanoma are CDKN2A and PTEN, mapping to 9p and 10q, respectively. Potential oncogenes include CDK4, NRAS, and epidermal growth factor receptor (EGFR), and various protein tyrosine kinases (PTK), such as EPH-A2 and EPH-B3, that are overexpressed in up to 90% of melanoma cell lines (reviewed inEasty and Bennett, 2000Easty D. Bennett D. Protein tyrosine kinases in malignant melanoma.Melanoma Res. 2000; 10: 401-411Crossref PubMed Scopus (114) Google Scholar). Interestingly, other PTKs, such as KIT and FES, are consistently downregulated in melanoma cell lines (Easty and Bennett, 2000Easty D. Bennett D. Protein tyrosine kinases in malignant melanoma.Melanoma Res. 2000; 10: 401-411Crossref PubMed Scopus (114) Google Scholar). CDKN2A, mapping to a frequently deleted region of 9p21, encodes p16INK4A (hereafter termed INK4A), a cyclin-dependent kinase (CDK) inhibitor that binds to and inhibits CDK4 and CDK6. When complexed with D-type cyclins these kinases drive entry into the cell cycle by phosphorylating the retinoblastoma family of proteins (pRb), which causes the release of E2F transcription factors and expression of E2F-regulated genes, thereby allowing progression from G1 to S phase. CDKN2A can be inactivated by several mechanisms, homozygous deletion, mutation or promoter methylation. Such alterations are frequently detected somatically in sporadic melanomas (e.g.,Dracopoli and Fountain, 1996Dracopoli N.C. Fountain J.W. CDKN2A mutations in melanoma.Cancer Surveys. 1996; 26: 115-132PubMed Google Scholar;Pollock and Trent, 2000Pollock P. Trent J. The, genetics, of, cutaneous, melanoma.Clin Lab Med. 2000; 20: 667-690PubMed Google Scholar), and constitutionally in familial melanoma patients (e.g.,Hussussian et al., 1994Hussussian C.J. Struewing J.P. Goldstein A.M. et al.Germline p16 mutations in familial melanoma.Nat Genet. 1994; 8: 15-21Crossref PubMed Scopus (1131) Google Scholar;Kamb et al., 1994Kamb A. Shattuck-Eidens D. Eeles R. et al.Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus.Nat Genet. 1994; 8: 23-26Crossref PubMed Scopus (761) Google Scholar). Loss of INK4A function partially inactivates the G1 block, and also leads to escape from cell senescence in culture. Further evidence implicating the INK4A/cyclin D/CDK4/pRb pathway comes from the finding of two rare germline CDK4 mutations in melanoma kindreds (Zuo et al., 1996Zuo L. Weger J. Yang Q. et al.Germline mutations of the p16 binding domain of CDK4 in familial melanoma.Nat Genet. 1996; 12: 97-99Crossref PubMed Scopus (667) Google Scholar;Soufir et al., 1998Soufir N. Avril M.F. Chompret A. et al.Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France.Hum Mol Genet. 1998; 7: 209-216Crossref PubMed Scopus (348) Google Scholar). Both mutations (R24C and R24H) prevent CDK4 from being inhibited by INK4A, underlining the importance of CDK4 as a second melanoma susceptibility gene. CDK4 can act as an oncogene in some tumors (mainly melanomas and gliomas) where its somatic overexpression usually results from gene amplification (He et al., 1994He J. Allen J.R. Collins V.P. Allalunis-Turner M.J. Godbout R. Day R.S. James C.D. CDK4 amplification is an alternative mechanism to p16 gene homozygous deletion in glioma cells lines.Cancer Res. 1994; 54: 5804-5807PubMed Google Scholar;Schmidt et al., 1994Schmidt E.E. Ichimura K. Reifenberger G. Collins V.P. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas.Cancer Res. 1994; 54: 6321PubMed Google Scholar). To date, activating mutations of CDK4 (e.g., R24C) have only been detected somatically in melanoma (e.g.,Tsao et al., 1998Tsao H. Benoit E. Sober A.J. Thiele C. Haluska F.G. Novel mutations in the p16/CDKN2A binding region of the cyclin dependent kinase-4 gene.Cancer Res. 1998; 58: 109-112PubMed Google Scholar). Mutations that affect the activity of any component of the INK4A/CDK4/cyclin D/pRb pathway have important ramifications for melanocyte transformation. Nearly all melanomas have been found to have a defect in this pathway (Castellano et al., 1997Castellano M. Pollock P.M. Walters M.K. et al.CDKN2A/p16 is inactivated in most melanoma cell lines.Cancer Res. 1997; 57: 4868-4875PubMed Google Scholar;Walker et al., 1998Walker G.J. Flores J.F. Glendening J.M. Lin A.H. Markl I.D. Fountain J.W. Virtually 100% of melanoma cell lines harbor alterations at the DNA level within CDKN2A, CDKN2B, or one of their downstream targets.Genes Chrom Cancer. 1998; 22: 157-163Crossref PubMed Scopus (114) Google Scholar). In a situation so far unique in the human and mouse genomes, CDKN2A also encodes a distinct and otherwise unrelated tumor suppressor protein, p14ARF (p19Arf in mouse; hereafter termed ARF), which acts through a different pathway involving stabilization of p53 through abrogation of HDM2 (Mdm2 in mouse)-induced p53 degradation (Zhang et al., 1998Zhang Y. Xiong Y. Yarbrough W.G. ARF promotes mdm2 degradation and stabilizes p53; ARF-INK4a locus deletion impairs both Rb and p53 tumour suppression pathways.Cell. 1998; 92: 725-734Abstract Full Text Full Text PDF PubMed Scopus (1397) Google Scholar). The alternatively spliced INK4A and ARF mRNA are transcribed off different first exons, and utilize the same second exon, but in a different reading frame (Figure 1). CDKN2A germline mutations in exon 1α affect only the INK4A transcript, whereas some of those occurring in exon 2 can affect both INK4A and ARF. Evidence is mounting that germline deletion (Bahuau et al., 1998Bahuau M. Vidaud D. Jenkins R.B. et al.Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.Cancer Res. 1998; 58: 2298-2303PubMed Google Scholar;Petronzelli et al., 2001Petronzelli F. Sollima D. Coppola G. Martini-Neri M.E. Neri G. Genuardi M. CDKN2A germline splicing mutation affecting both p16 (ink4) and p14 (arf) RNA processing in a melanoma/neurofibroma kindred.Genes Chromosom Cancer. 2001; 31: 398-401Crossref PubMed Scopus (57) Google Scholar;Randerson-Moor et al., 2001Randerson-Moor J.A. Harland M. Williams S. et al.A germline deletion of p14 (ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family.Hum Mol Genet. 2001; 10: 55-62Crossref PubMed Scopus (231) Google Scholar) or mutation (Rizos et al., 2001bRizos H. Puig S. Badenas C. et al.A melanoma-associated germline mutation in exon 1b inactivates p14ARF.Oncogene. 2001; 20: 5543-5547Crossref PubMed Scopus (157) Google Scholar) of exon 1β may also predispose to melanoma as well as tumors of the neural system. Somatic exon 1β mutations have not been detected in uncultured melanomas, although melanoma cell lines have been reported with specific deletions of exon 1β, leaving INK4A intact (Kumar et al., 1998Kumar R. Sauroja I. Punnonen K. Jansen C. Hemminki K. Selective deletion of exon 1 beta of the p19ARF gene in metastatic melanoma cell lines.Genes Chrom Cancer. 1998; 23: 273-277Crossref PubMed Scopus (71) Google Scholar). Regulation of the G1–S phase cell cycle transition is made more complex by the existence of other CDK4 inhibitors, including the INK4-specific inhibitors p15INK4B, p18INK4C, and p19INK4D, and the less specific CIP1/KIP1 inhibitors p21CIP1, p27KIP1, and p57KIP2, which bind many CDKs (Figure 2). The latter can bind to, but do not inhibit CDK4. To proceed fully through G1, complete phosphorylation and inactivation of pRb may require the kinase activity of both CDK4 and CDK2, made possible in part by reassortment of inhibitors, particularly p27KIP1 shuffling between cyclin D/CDK4 and cyclin E/CDK2 complexes, leading to activation of the latter (reviewed inSherr and Roberts, 1999Sherr C. Roberts J. CDK inhibitors. positive and negative regulators of G1-S phase progression.Genes Dev. 1999; 13: 1501-1512Crossref PubMed Scopus (5131) Google Scholar). In effect, CDK4 can also help promote G1–S phase progression by titrating p27KIP1 away from CDK2/cyclin E complexes. CDKN2A is the only CDK-inhibitor gene mutated in human melanoma, and none of the knockout mouse models of the other inhibitors develop skin cancers, although some are susceptible to the development of other tumor types, particularly of neuroendocrine origin (reviewed inChin et al., 1998Chin L. Pomerantz J. DePinho R. The INK4a/ARF tumor suppressor: one gene-two products-two pathways.Trends Biochem Sci. 1998; 23: 291-296Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar). Cytogenetic deletions and loss of heterozygosity on chromosome 10q is a common feature of human melanoma. A candidate tumor suppressor, PTEN, was isolated from 10q23, and subsequently shown to be mutated or deleted in many tumor types (reviewed inCantley and Neel, 1999Cantley L.C. Neel B.G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway.Proc Natl Acad Sci USA. 1999; 96: 4240-4245Crossref PubMed Scopus (1745) Google Scholar). Germline PTEN mutations have been detected in several familial hamartoma syndromes, including Cowden disease and Bannayan–Riley–Ruvulcaba syndrome (reviewed inDiLiberti, 1998DiLiberti J.H. Inherited macrocephaly–hamartoma syndromes.Am J Med Genet. 1998; 79: 284-290Crossref PubMed Scopus (39) Google Scholar). In the largest study of PTEN in melanoma carried out to date (Pollock et al., 2002Pollock P. Walker G. Glendening M. Que Noy T. Bloch N. Fountain J. Hayward N. PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines.Melanoma Res. 2002Crossref Scopus (56) Google Scholar), deletion or mutation of the gene was detected in 23% of melanoma cell lines, which, in terms of mutation frequency, makes it possibly the most important “classical”TSG gene in melanoma after CDKN2A (although downregulation by mechanisms other than mutation or deletion may be more common for some PTK, e.g., KIT and FES). PTEN functions by dephosphorylating the lipid second messenger phosphotidylinositol (PI) 3,4,5 triphosphate and other proteins in the cascade that controls aspects of cell growth and survival, including apoptosis (reviewed inMaehama and Dixon, 1999Maehama T. Dixon J.E. PTEN: a tumour suppressor that functions as a phospholipid phosphatase.Trends Cell Biol. 1999; 9: 125-128Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar). One of the major PTEN pathways involves Ras, PI3K, and AKT (PKB). Uncontrolled activity of any of these proteins is oncogenic. Because PTEN and NRAS mutations seem to be mutually exclusive in human melanoma, it is thought that they may act through the same pathway (Tsao et al., 2000Tsao H. Zhang X. Fowlkes K. Haluska F.G. Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines.Cancer Res. 2000; 60: 1800-1804PubMed Google Scholar). This is supported by functional evidence showing that PTEN is also capable of suppressing activated Ras-mediated transformation of NIH3T3 cells (Tolkacheva and Chan, 2000Tolkacheva T. Chan A.M. Inhibition of H-Ras transformation by the PTEN/MMAC1/TEP1 tumor suppressor gene.Oncogene. 2000; 19: 680-689Crossref PubMed Scopus (63) Google Scholar;Tsao et al., 2000Tsao H. Zhang X. Fowlkes K. Haluska F.G. Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines.Cancer Res. 2000; 60: 1800-1804PubMed Google Scholar), associated with suppression of the PI3K signaling cascade stimulated by Ras. Thus the activation of Ras and loss of PTEN may be substantially equivalent, at least in terms of their actions through the PI3K pathway. PTEN has also been shown to induce cell cycle arrest mediated by PI3K in a pRb-dependent manner (Paramio et al., 1999Paramio J.M. Navarro M. Segrelles C. Gomez-Casero E. Jorcano J.L. PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein.Oncogene. 1999; 18: 7462-7468Crossref PubMed Scopus (106) Google Scholar), possibly by downregulating cyclin D and upregulating p27Kip1 (Atkas et al., 1997Atkas H. Cai H. Cooper G.M. Ras links factor signalling to the cell cycle machinery via regulation of cyclin D1 and Cdk inhibitor p27.Mol Cell Biol. 1997; 17: 3850-3857Crossref PubMed Scopus (370) Google Scholar;Weng et al., 2001Weng L.P. Brown J.L. Eng C. PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model.Hum Mol Genet. 2001; 10: 599-604Crossref PubMed Google Scholar). Activating mutations of the Ras family (in general Nras, but to a lesser extent Hras and Kras) are detected in about 15% of melanocytic lesions (Van Elsas et al., 1996Van Elsas A. Zerp S.F. Van der Fliers S. et al.Relevance of ultraviolet-induced N-ras oncogene point mutations in development of primary cutaneous melanoma.Am J Pathol. 1996; 149: 883-893PubMed Google Scholar), but appear to be a late event in melanoma progression. Although the genetic evidence outlined above points to a role for the Ras/PI3K/Akt pathway in melanoma, Ras has multiple effectors (reviewed inHunter, 1997Hunter T. Oncoprotein networks.Cell. 1997; 88: 333-346Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar;Sears and Nevins, 2002Sears R. Nevins J. Signalling networks that link cell proliferation and cell fate.J Biol Chem. 2002; 277: 11617-11620Crossref PubMed Scopus (276) Google Scholar) that may also stimulate other pathways involved in melanoma development. These may include the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway that promotes transcription of CCND1 (the gene encoding cyclin D1), and also assists in post-translational assembly of cyclin D/CDK4 complexes. Stimulation of CCND1 transcription is also mediated by activation of another Ras effector, RalGDS. Furthermore, Ras stimulation through the RhoA GTPase pathway can induce degradation of p27KIP1 (Hu et al., 1999Hu W. Bellone C.J. Baldassare J.J. RhoA stimulates p27 (Kip) degradation through its regulation of cyclin E/CDK2 activity.J Biol Chem. 1999; 274: 3396-3401Crossref PubMed Scopus (106) Google Scholar), thus releasing inhibition of cyclin E/CDK2 activity needed for cells to proceed into S-phase. Ras effectors are capable of inducing senescence, apoptosis, or activating cell proliferation, with the various effector pathways collaborating to achieve specificity of signaling dependent on the setting (Sears and Nevins, 2002Sears R. Nevins J. Signalling networks that link cell proliferation and cell fate.J Biol Chem. 2002; 277: 11617-11620Crossref PubMed Scopus (276) Google Scholar). Attempts to induce transformation of melanocytes in mice have, in general, utilized transgenic methods to overexpress oncogenes (Table I), and homologous recombination techniques to “knock out” portions of TSG or “knock in” mutations of either of TSG or oncogenes (Table II).Table ITransgenic mouse models of melanomaGenetic modification (promoter/gene)StrainSpontaneous melanomaTumor typeUV-induced melanomasa% of mice with UV-induced melanomas; see Table III for summary of UV exposure protocols.UV wavelengthsUV protocolReferenceTyr-SV40 Tag (high expresser)C57/BL6Yes, up to 100% from 4 wkPredominantly OMM, but some CMM, metastaticMortality too high to be assessedBradl et al., 1991Bradl M. Klein-Szanto A. Porter S. Mintz B. Malignant melanoma in transgenic mice.Proc Natl Acad Sci USA. 1991; 88: 164-168Crossref PubMed Scopus (131) Google ScholarKlein-Szanto et al., 1991Klein-Szanto A. Bradl M. Porter S. Mintz B. Melanosis and associated tumors in transgenic mice.Proc Natl Acad Sci USA. 1991; 88: 169-173Crossref PubMed Scopus (42) Google ScholarTyr-SV40 Tag (low expresser)C57/BL6Infrequent OMM, no CMM26%CMM; latency 37–98 wk70% UVB 280–320nm; 29.7% UVA, 320–380 nm3.28 kJ per m2 to 4 d old neonates, repeated for 5 dKlein-Szanto et al., 1994Klein-Szanto A.J. Silvers W.K. Mintz B. Ultraviolet radiation-induced malignant skin melanoma in melanoma-susceptible transgenic mice.Cancer Res. 1994; 54: 4569-4572PubMed Google ScholarKelsall and Mintz, 1998Kelsall S.R. Mintz B. Metastatic cutaneous melanoma promoted by ultraviolet radiation in mice with transgene-initiated low melanoma susceptibility.Cancer Res. 1998; 58: 4061-4065PubMed Google ScholarTyrp1- SV40 TagNMRI/HANYes, 100% OMM by 3 moMetastatic RPE tumoursNot assessedPenna et al., 1998Penna D. Schmidt A. Beermann F. Tumors of the retinal pigment epithelium metastasise to the inguinal lymph nodes and spleen in tyrosinase-related protein 1/SV40 T antigen transgenic mice.Oncogene. 1998; 17: 2601-2607Crossref PubMed Scopus (33) Google ScholarMt1-RetBALB/C, C57BL6Yes, up to 93% OMM by 5 moCMM and OMM, not metastaticIncreased invasiveness of tumorsBroad-spectrum: 250–400 nm (60% UVB)Incremental 2.25–6 kJ per m2 tri-weekly for 34 wkIwamoto et al., 1991Iwamoto T. Takahashi M. Ito M. et al.Aberrant melanogenesis and melanocytic tumour development in transgenic mice that carry a metallothionein/ret fusion gene.EMBO J. 1991; 10: 3167-3175PubMed Google ScholarKato et al., 2000Kato M. Liu W. Akhand A.A. Hossain K. Takeda K. Takahashi M. Nakashima I. Ultraviolet radiation induces both full activation of ret kinase and malignant melanocytic tumor promotion in RFP-RET-transgenic mice.Invest Dermatol. 2000; 115: 1157-1158Crossref PubMed Scopus (21) Google ScholarTyrp1-RetNMRIYes, OMMNot assessedNot assessedSchmidt et al., 1999Schmidt A. Tief K. Yavuzer U. Beermann F. Ectopic expression of ret results in microphthalmia and tumors of the retinal pigment epithelium.Int J Cancer. 1999; 80: 600-605Crossref PubMed Scopus (21) Google ScholarTyr-Hras (G12V)C3H12% OMM, no CMMMelanocyte hyperplasia20% naevi and CMM, only on albino background90% UVB 280–340 nmBi-weekly for 38 wk 5.6–8.06 kJ per m2Broome Powell et al., 1995Broome Powell M. Hyman P. Bell O.D. et al.Hyperpigmentation and melanocytic dysplasia in transgenic mice expressing human T24 Hras gene regulated by a mouse tyrosinase promoter.Mol Carcinogen. 1995; 12: 82-90Crossref PubMed Scopus (68) Google Scholar, Broome-Powell et al., 1999Broome-Powell M. Gause P. Hyman P. Gregus J. Lluria-Prevatt M. Nagle R. Bowden G.T. Induction of melanoma in TPras transgenic mice.Carcinogenesis. 1999; 20: 1747-1753Crossref PubMed Scopus (76) Google ScholarTyr-Hras (G12V)mixedVery rarelyMelanocyte hyperplasiaNot assessedChin et al., 1997Chin L. Pomerantz J. Polsky D. et al.Cooperative effects of INK4a and ras in melanoma susceptibility in vivo.Genes Dev. 1997; 11: 2822-2834Crossref PubMed Scopus (349) Google ScholarMt1-Hgf/SfFVBYes, 22%, mean age of onset 15.6 moMelanocyte hyperplasia, CMM, metastaticNo increase in CMM240–400 nm2.25–6 kJ per m2 tri-weekly for 17 wkOtsuka et al., 1998Otsuka T. Takayama H. Sharp R. et al.c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype.Cancer Res. 1998; 58: 5157-5167PubMed Google ScholarNoonan et al., 2000Noonan F.P. Otsuka T. Bang S. Anver M. Merlino G. Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth factor/scatter factor transgenic mice.Cancer Res. 2000; 60: 3738-3743PubMed Google ScholarMt1-Hgf/SfFVBAs aboveAs aboveCMM in 80% within 12 mo240–400 nm9.2 kJ per m2, 1 dose to 4 d old neonatesNoonan et al., 2001Noonan F. Recio J. Takayama H. et al.Neonatal sunburn and melanoma in mice.Nature. 2001; 413: 271-272Crossref PubMed Scopus (311) Google ScholarKrt4-ScfC57BLNoEpidermal melanocytosisNot assessedKunisada et al., 1998Kunisada T. Lu S.Z. Yoshida H. et al.Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor.J Exp Med. 1998; 187: 1565-1573Crossref PubMed Scopus (162) Google Scholara % of mice with UV-induced melanomas; see Table III for summary of UV exposure protocols. Open table in a new tab Table IIKnockout/knockin mouse models of melanomaGenetic modificationSpontaneous melanomasaPercentage of mice that developed CMM. Blank field = not assessed.Induced melanomasSpontaneous tumors (nonmelanoma)bOverall percentage of animals with nonmelanoma tumors, with most common tumor types listed for each model: FS, fibrosarcoma; S, other sarcoma; P, papilloma; L, lymphoma; A, adenoma; G, glioma; SCC: squamous cell carcinoma; E, endocrine tumors.Induced tumors (nonmelanoma)bOverall percentage of animals with nonmelanoma tumors, with most common tumor types listed for each model: FS, fibrosarcoma; S, other sarcoma; P, papilloma; L, lymphoma; A, adenoma; G, glioma; SCC: squamous cell carcinoma; E, endocrine tumors.MEF/cultured tumor cellsReferenceInk4a–/–:Arf–/–, del Cdkn2a exons 2 and 3NoneNone69% at average of 29 wk, FS, L, S90% at 20 wk with DMBA/UVB;cWavelengths used, 295–310 nm (UVB); 27 exposures 1–7 kJ per m2 beginning at postnatal days 4–8; strain, C57BL/6. FS, L, SSCImmortal and transformedby activated HrasSerrano et al., 1996Serrano M. Lee H.-W. Chin L. Cordon-Cardo C. Beach D. DePinho R. Role of INK4a locus in tumour suppression and cell mortality.Cell. 1996; 85: 27-37Abstract Full Text Full Text PDF PubMed Scopus (1408) Google ScholarArf–/–, del exon 1βNoneNone33% at 24 wk; FS, L, SSC, G, S, A82% at 20 wk with DMBA; SCC, L, SImmortal and transformedby activated HrasKamijo et al., 1997Kamijo T. Zindy F. Roussel M. et al.Tumour suppression at the mouse INK4a" @default.
• W2057394091 created "2016-06-24" @default.
• W2057394091 creator A5043115524 @default.
• W2057394091 creator A5047949525 @default.
• W2057394091 date "2002-10-01" @default.
• W2057394091 modified "2023-10-03" @default.
• W2057394091 title "Pathways to Melanoma Development: Lessons from the Mouse" @default.
• W2057394091 cites W1270711560 @default.
• W2057394091 cites W134922517 @default.
• W2057394091 cites W140694299 @default.
• W2057394091 cites W1483388049 @default.
• W2057394091 cites W1487917997 @default.
• W2057394091 cites W1489145507 @default.
• W2057394091 cites W1502422706 @default.
• W2057394091 cites W1520222296 @default.
• W2057394091 cites W1589289370 @default.
• W2057394091 cites W1629158872 @default.
• W2057394091 cites W1804201762 @default.
• W2057394091 cites W1946633045 @default.
• W2057394091 cites W1970941955 @default.
• W2057394091 cites W1971512164 @default.
• W2057394091 cites W1972187446 @default.
• W2057394091 cites W1973886069 @default.
• W2057394091 cites W1978775178 @default.
• W2057394091 cites W1983751803 @default.
• W2057394091 cites W1984418041 @default.
• W2057394091 cites W1986512406 @default.
• W2057394091 cites W1992030386 @default.
• W2057394091 cites W1992270075 @default.
• W2057394091 cites W1993781672 @default.
• W2057394091 cites W2002045623 @default.
• W2057394091 cites W2003223749 @default.
• W2057394091 cites W2005580242 @default.
• W2057394091 cites W2014309354 @default.
• W2057394091 cites W2017117125 @default.
• W2057394091 cites W2017235640 @default.
• W2057394091 cites W2019573100 @default.
• W2057394091 cites W2020812965 @default.
• W2057394091 cites W2020891498 @default.
• W2057394091 cites W2023325850 @default.
• W2057394091 cites W2026692890 @default.
• W2057394091 cites W2030317576 @default.
• W2057394091 cites W2032408706 @default.
• W2057394091 cites W2043806397 @default.
• W2057394091 cites W2044761914 @default.
• W2057394091 cites W2047190080 @default.
• W2057394091 cites W2049085719 @default.
• W2057394091 cites W2049150304 @default.
• W2057394091 cites W2051506850 @default.
• W2057394091 cites W2052014900 @default.
• W2057394091 cites W2052276955 @default.
• W2057394091 cites W2063367127 @default.
• W2057394091 cites W2076316644 @default.
• W2057394091 cites W2082224552 @default.
• W2057394091 cites W2082657194 @default.
• W2057394091 cites W2085761836 @default.
• W2057394091 cites W2086390568 @default.
• W2057394091 cites W2086773265 @default.
• W2057394091 cites W2089143505 @default.
• W2057394091 cites W2091643502 @default.
• W2057394091 cites W2100646314 @default.
• W2057394091 cites W2106211503 @default.
• W2057394091 cites W2110128078 @default.
• W2057394091 cites W2111062014 @default.
• W2057394091 cites W2119730508 @default.
• W2057394091 cites W2121619780 @default.
• W2057394091 cites W2122889044 @default.
• W2057394091 cites W2135981246 @default.
• W2057394091 cites W2139052774 @default.
• W2057394091 cites W2139402152 @default.
• W2057394091 cites W2139584813 @default.
• W2057394091 cites W2147822352 @default.
• W2057394091 cites W2152534875 @default.
• W2057394091 cites W2161706145 @default.
• W2057394091 cites W2162851671 @default.
• W2057394091 cites W2164263233 @default.
• W2057394091 cites W2165712565 @default.
• W2057394091 cites W2314257098 @default.
• W2057394091 cites W2316848840 @default.
• W2057394091 cites W2319636149 @default.
• W2057394091 cites W2329587797 @default.
• W2057394091 cites W4211261801 @default.
• W2057394091 cites W4232555387 @default.
• W2057394091 cites W91777371 @default.
• W2057394091 doi "https://doi.org/10.1046/j.1523-1747.2002.00217.x" @default.
• W2057394091 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/12406321" @default.
• W2057394091 hasPublicationYear "2002" @default.
• W2057394091 type Work @default.
• W2057394091 sameAs 2057394091 @default.
• W2057394091 citedByCount "66" @default.
• W2057394091 countsByYear W20573940912012 @default.
• W2057394091 countsByYear W20573940912015 @default.
• W2057394091 countsByYear W20573940912016 @default.
• W2057394091 countsByYear W20573940912017 @default.
• W2057394091 countsByYear W20573940912018 @default.
• W2057394091 countsByYear W20573940912020 @default.
• W2057394091 countsByYear W20573940912022 @default.
• W2057394091 crossrefType "journal-article" @default.

• next