These data show that a change in MITF transcriptional activity from repression to activation of S100A4 that results from a point mutation in MITF alters melanoma invasive ability.
Melanoma development and progression is thought to be the result of a multi-step accumulation of genetic damage, with loss of heterozygosity in chromosome 9p (MTS1) frequently described.
Germ-line mutations in the CDKN2A tumor-suppressor gene (also known as p16, p16INK4a, and MTS1) have been linked to the development of melanoma in some families with inherited melanoma.
These data indicate correlation between gradual loss of expression of the MTS1 locus and progression of melanoma, further supporting an emerging role for the gene in the malignant transformation of melanocytes.
The p16/CDKN2(MTS1) gene encoding for the p16 inhibitor of cyclin D/CDK4 complexes is frequently mutated and deleted in a large fraction of melanoma cell lines, and p16 germline mutations have also been observed in familial melanomas.
The p16 (CDKN2/MTS1/INK4a) malignant melanoma susceptibility gene was analyzed in 10 melanoma kindreds from southern Sweden using single-stranded conformation polymorphism analysis of all three exons and flanking intron regions followed by sequence analysis.
The latter finding further supports the hypothesis that the 9p21 region may contain one or more tumor suppressor genes (e.g., MTS1/CDNK2) involved in the pathogenesis of melanoma.
The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene.