Id2 suppression of p15 counters TGF-beta-mediated growth inhibition of melanoma cells.

Proliferative resistance to transforming growth factor beta (TGF-beta) is regarded as a critical turning point in the malignant progression of many cancer types. In melanoma this resistance is associated with more aggressive metastatic behaviour. A recent study by our group identified proliferative and invasive subtypes of melanoma cultures and found that these are, respectively, susceptible and resistant to TGF-beta suppression of proliferation. Here, using previously characterised proliferative and invasive phenotype melanoma cultures, we explored molecular responses involved in modulating susceptibility to TGF-beta-mediated inhibition of proliferation. The Id2 gene was identified as being expressed more strongly in invasive phenotype cells less susceptible to TGF-beta repression than in proliferative phenotype cells. We correlated TGF-beta repression of Id2 gene expression in proliferative phenotype cells with p15(Ink4b) induction and cell cycle arrest. Furthermore, ectopic Id2 expression in proliferative phenotype cells counteracted p15(Ink4b) induction and consequently protected them from TGF-beta-mediated inhibition of proliferation. We conclude that transition to increased aggressiveness in melanoma cells requires Id2 upregulation to suppress TGF-beta induction of p15(Ink4b) and thus help to circumvent TGF-beta-mediated inhibition of proliferation.