Localization of a CDKN2 gene in linkage group V of Xiphophorus fishes defines it as a candidate for the DIFF tumor suppressor

Kazianis, Steven; Gutbrod, Heidrun; Nairn, Rodney S.; McEntire, Brenda B.; Coletta, Luis Della; Walter, Ronald B.; Borowsky, Richard; Woodhead, Avril D.; Setlow, R. B.; Schartl, Manfred; Morizot, Donald C.

doi:10.1002/(sici)1098-2264(199807)22:3<210::aid-gcc6>3.3.co;2-e

Cited by 14 publications

(43 citation statements)

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“…The 5' flanking region contains a variable copy number GT-repeat that is highly polymorphic between species, enabling quick and reliable allele-specific genotyping. The PCR conditions conformed to those previously published (Kazianis et al, 1998). Amplification from X. maculatus (Jp 163 A) resulted in a 1220-bp product, whereas a 1079-bp band was derived from X. couchianus.…”

Section: Dna Isolation and Cdkn2x Genotypingmentioning

confidence: 95%

“…In addition, strong associations have been shown between LG V genotypes and spontaneous or UV-induced melanoma formation in several distinct Xiphophorus genetic crosses, all involving the platyfish X. maculatus (Kazianis et al, 1998). The tumor suppressor gene candidate CDKN2X maps to this autosomal region (Nairn et al, 1996a) and has shown strong genetic associations with melanotic phenotype and even stronger associations with melanoma formation (Kazianis et al, 1998;Nairn et al, 1996a). Thus, CDKN2X is considered a candidate for the classically defined Diff tumor suppressor gene (Kazianis et al, 1999).…”

Section: Mnu-induced Carcinogenesis In Xiphophorusmentioning

confidence: 95%

“…Xiphophorus LG V harbors a locus referred to as Diff which has been implicated in determining the state of differentiation of melanistic pigment cells (Ahuja et al, 1980;Vielkind, 1976). In addition, strong associations have been shown between LG V genotypes and spontaneous or UV-induced melanoma formation in several distinct Xiphophorus genetic crosses, all involving the platyfish X. maculatus (Kazianis et al, 1998). The tumor suppressor gene candidate CDKN2X maps to this autosomal region (Nairn et al, 1996a) and has shown strong genetic associations with melanotic phenotype and even stronger associations with melanoma formation (Kazianis et al, 1998;Nairn et al, 1996a).…”

Section: Mnu-induced Carcinogenesis In Xiphophorusmentioning

confidence: 98%

“…Such a result is striking and consistent with a locus within LG V playing a role in the development of melanosis and being associated with the Af pigment pattern. There have been several previous reports (involving different genetic crosses and pigment patterns) of an association of Xiphophorus LG V genotypic data and melanoma formation and for spontaneous and UV-induced melanotic hyperplasia, although involvement with the Af pigment pattern has not been previously noted (Ahuja et al, 1980;Fornzler et al, 1991;Kazianis et al, 1998;Morizot and Siciliano, 1983;). …”

Section: Nificant (mentioning

confidence: 99%

“…Melanomas derived within such hybrid crosses are clearly genetically predetermined, as was demonstrated for several Xiphophorus tumor models (Nairn et al, 1996b;Schartl, 1995;Vielkind et al, 1989). A candidate tumor suppressor gene, CDKN2X, which maps to Xiphophorus linkage group V (LG V) within a genomic region implicated in melanoma tumor suppression and pigment pattern regulation, was cloned (Kazianis et al, 1998(Kazianis et al, , 1999Vielkind, 1976). This gene shows structural similarity to the human CDKN2A (P16) locus, which is presently thought to be involved in suppressing human melanoma and other tumors as well (Chin et al, 1998;Ruas and Peters, 1998).…”

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MNU Induction of Neoplasia in a Platyfish Model

Kazianis

Gimenez-Conti

Setlow

et al. 2001

Laboratory Investigation

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SUMMARY:Interspecific hybrid crosses between members of the fish genus Xiphophorus have been used for over 70 years to study the genetic aspects of melanoma formation. In the well-established "Gordon-Kosswig" cross, the platyfish X. maculatus is outcrossed to the swordtail X. helleri, and the resulting backcross segregants spontaneously develop melanoma. We recently produced a distinct cross between X. maculatus and another platyfish species, X. couchianus. X. maculatus strain Jp 163 A is homozygous for several X-linked pigment pattern genes, including the Spotted dorsal (Sd), Dorsal red (Dr), and Anal fin spot (Af). Af is a sex-limited trait, coding exclusively for melanophores distributed on the modified anal fin or "gonopodium" in the adult male fish. Within F 1 and BC 1 hybrids (to X. couchianus), the Sd pigment pattern is phenotypically suppressed, whereas Dr and Af are enhanced. We exposed BC 1 hybrids to the direct-acting carcinogen N-methyl-N-nitrosourea (MNU). Treatment led to the development of schwannomas, fibrosarcomas, and retinoblastomas. In addition, numerous MNU-treated males that inherited Af developed a pronounced melanotic phenotype, with melanin-containing cells oftentimes totally covering the gonopodium and extending further to grow within the ventral regions of the fish. Genetic linkage analysis of the BC 1 hybrids revealed a significant (p Ͻ 0.01) association between CDKN2X genotype and the phenotypic degree of melanization. Such an association is consistent with a locus within linkage group V playing a role in the development of melanosis and delineates three genetic preconditions and a carcinogenic scheme resulting in melanosis of the ventral regions of hybrid fish. The overall study further alludes to the potential of using Xiphophorus fish to study carcinogenic mechanisms for tumors other than melanoma (schwannoma, fibrosarcoma, and retinoblastoma) and should enable extensive pathologic and molecular genetic studies of derived neoplastic abnormalities. (Lab Invest 2001, 81:1191-1198.

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Section: Dna Isolation and Cdkn2x Genotypingmentioning

confidence: 95%

Section: Mnu-induced Carcinogenesis In Xiphophorusmentioning

confidence: 95%

Section: Mnu-induced Carcinogenesis In Xiphophorusmentioning

confidence: 98%

Section: Nificant (mentioning

confidence: 99%

mentioning

confidence: 99%

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MNU Induction of Neoplasia in a Platyfish Model

Kazianis

Gimenez-Conti

Setlow

et al. 2001

Laboratory Investigation

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Melanoma susceptibility and cell cycle genes in Xiphophorus hybrids

Butler

Trono

Beard

et al. 2007

Molecular Carcinogenesis

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Xiphophorus interspecies hybrids provide genetically defined models of both spontaneous and inducible melanomagenesis. In both models, backcrossing F(1) hybrids of different strains of X. maculatus and X. helleri to a X. helleri parental fish results in segregation of melanoma susceptibility, fitting a Mendelian two-gene inheritance model. The sex-linked Xmrk oncogene is required for melanoma development in both crosses. The Xiphophorus CDKN2A/B gene, which is homologous to mammalian CDKN2A/B cyclin-dependent kinase inhibitors (p16 and p15), is a candidate melanoma susceptibility gene. In this model, tumor susceptibility segregates with homozgyosity for CDKN2A/B from the recurrent X. helleri parent in backcross hybrids. We found that both CDKN2A/B mRNA and protein are highly overexpressed in melanoma. Because the p13 protein product of CDKN2A/B is a putative regulator of the G1 checkpoint, we investigated expression of other components of Xiphophorus G1 checkpoint control. By real-time PCR analysis, retinoblastoma gene (RB) is consistently expressed twofold higher in both tumors and melanized skin than in normal tissue, indicating that RB is not downregulated by the overexpression of CDKN2A/B in Xiphophorus melanoma. We also found a significant correlation between the quantitative level of CDKN2A/B and Xmrk RNA in tumors, suggesting a functional relationship between Xmrk and CDKN2A/B expression. Although X. helleri CDKN2A/B protein contains a non-conservative substitution, the biochemical function appears to show little overt defect. These studies indicate that in Xiphophorus melanoma, CDKN2A/B is functionally insufficient to mediate cell-cycle arrest in the presence of Xmrk.

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Molecular genetic analysis of the melanoma regulatory locus in Xiphophorus interspecies hybrids

Boswell

et al. 2017

Molecular Carcinogenesis

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Development of spontaneous melanoma in Xiphophorus interspecies backcross hybrid progeny, (X. hellerii × [X. maculatus Jp 163 A × X. hellerii]) is due to Mendelian segregation of a oncogene (xmrk) and a molecularly uncharacterized locus, called R(Diff), on LG5. R(Diff) is thought to suppresses the activity of xmrk in healthy X. maculatus Jp 163 A parental species that rarely develop melanoma. To better understand the molecular genetics of R(Diff), we utilized RNA-Seq to study allele-specific gene expression of spontaneous melanoma tumors and corresponding normal skin samples derived from 15 first generation backcross (BC1) hybrids and 13 fifth generation (BC5) hybrids. Allele-specific expression was determined for all genes and assigned to parental allele inheritance for each backcross hybrid individual. Results showed that genes residing in a 5.81 Mbp region on LG5 were exclusively expressed from the X. hellerii alleles in tumor-bearing BC1 hybrids. This observation indicates this region is consistently homozygous for X. hellerii alleles in tumor bearing animals, and therefore defines this region to be the R(Diff) locus. The R(Diff) locus harbors 164 gene models and includes the previously characterized R(Diff) candidate, cdkn2x. Twenty one genes in the R(Diff) region show differential expression in the tumor samples compared to normal skin tissue. These results further characterize the R(Diff) locus and suggest tumor suppression may require a multigenic region rather than a single gene variant. Differences in gene expression between tumor and normal skin tissue in this region may indicate interactions among several genes are required for backcross hybrid melanoma development.

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Localization of a CDKN2 gene in linkage group V of Xiphophorus fishes defines it as a candidate for the DIFF tumor suppressor

Cited by 14 publications

References 0 publications

MNU Induction of Neoplasia in a Platyfish Model

MNU Induction of Neoplasia in a Platyfish Model

Melanoma susceptibility and cell cycle genes in Xiphophorus hybrids

Molecular genetic analysis of the melanoma regulatory locus in Xiphophorus interspecies hybrids

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