High expression of cyclin E and G1 CDK and loss of function of p57(KIP2) are involved in proliferation of malignant sporadic adrenocortical tumors

Maternal loss of heterozygosity (LOH) of the 11p15 region and overexpressio n of the insulin-like growth factor (IGF)-II gene are associated with the m alignant phenotype in sporadic adrenocortical tumors. In the imprinted 11p1 5 region, the p57(KIP2) gene is maternally expressed and encodes a cyclin-d ependent kinase (CDK) inhibitor involved in G(1)/S phase of the cell cycle. We hypothesized that maternal LOH in malignant adrenocortical tumors could be responsible for loss of p57(KIP2) gene expression and, thus, could favor progression through the cell, cycle. We investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal expression of the IGF-II gene (mainly benign) and 20 with IGF-II ge ne overexpression (mainly malignant)], and the human adrenocortical tumor c ell Line NCI H295R for expression of the p57(KIP2) gene, G1 cyclins (cyclin D2 and E) and G1 CDK(CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin-CDK complexes. The expression of p57(KIP2), G1 cyclins, and G1 CDKs in benign tumors was s imilar to that in normal adrenal tissues, as were kinase activities of G1 c yclin-CDK complexes. By contrast, abrogation of the p57(KIP2) gene expressi on and increased expression of G1 cyclins (cyclin E) and G1 CDKs (CDK2 and CDK4) were associated with high activity of G1 cyclin-CDK complexes in mali gnant tumors and in the H295R cell Line. These data suggest that the p57(KIP2) gene might act as a tumor suppressor gene in adrenocortical tumors. Maternal LOH with duplication of the paterna l allele or pathological functional imprinting of the 11p15 region are resp onsible for loss of expression of the p57(KIP2) gene and increased expressi on of the IGF-II gene. Consequently, both events favor cell proliferation i n malignant adrenocortical tumors.