p16(MTS-1/CDKN2/INK4a) in cancer progression

Since its discovery as an inhibitor of cyclin-dependent kinases 4 and 6, the tumor suppressor pie has continued to gain widespread importance in cancer. The high frequency of deletions of p16 in tumor cell lines first suggested an important role for p16 in carcinogenesis. This initial genetic evidence was subsequently strengthened by numerous studies documenting p16 inactivation in kindreds with familial melanoma. Moreover, a high frequency of p16 gene alterations was found in primary tumors, while recent studies have identified p16 promoter methylation as a major mechanism of tumor-suppressor-gene silencing. Additional insight into pie's role in cancer has come from the genetic analysis of precancerous lesions and various tissue culture models. It is now believed that loss of pie is an early and often critical event in tumor progression. Consequently, pie is a major tumor-suppressor gene whose frequent loss occurs early in many human cancers. (C) 2001 Academic Press.