The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas

The helix-loop-helix transcription factor Idl coordinates cell growth and d ifferentiation pathways within mammalian cells and has been implicated in r egulating GI-S phase cell cycle transitions. Recently Idl has been shown to repress Ets- and E-protein-mediated transactivation of p16/Ink4a. Because the p16/Ink4a protein has been demonstrated to be inactivated in subsets of familial and sporadic melanomas, we sought to determine whether Idl regula tion of p16/Ink4a expression might be involved in the development of this h uman tumor. Here we evaluate 21 melanocytic lesions at various stages of ma lignant progression from common melanocytic nevi to metastatic melanomas an d examine these lesions for Idl and p16/Ink4a expression. We demonstrate th at Idl expression correlates with loss of p16/Ink4a expression in melanoma in situ; However, more advanced stages of melanoma do not express Idl excep t within perivascular regions, despite overall decreased p16/Ink4a expressi on in these lesions. Microdissected lesions were evaluated for p16/Ink4a se quence, and invasive melanomas that did not express Idl were found to have sustained inactivating p16/Ink4a mutations. These data suggest a role for I dl in regulating p16/Ink4a expression in early melanomas and demonstrate th at later genetic changes may provide for irreversible loss of p16 expressio n in advanced stages of this tumor.