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High Expression of Cyclin E and G1 CDK and Loss of Function of p57^KIP2 Are Involved in Proliferation of Malignant Sporadic Adrenocortical Tumors¹

Laboratoire d’Explorations Fonctionnelles Endocriniennes and INSERM U515 (N.B., V.G., A.L., Y.L.B., C.G.), Hôpital Trousseau; and Clinique des Maladies Endocriniennes et Métaboliques (X.B.), Hôpital Cochin, AP-HP PARIS, France

Address correspondence and requests for reprints to: Dr. Christine Gicquel, Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 26 Avenue Arnold Netter, 75012 Paris, France. E-mail: christine.gicquel{at}trs.ap-hop-paris.fr

Maternal loss of heterozygosity (LOH) of the 11p15 region and overexpression of the insulin-like growth factor (IGF)-II gene are associated with the malignant phenotype in sporadic adrenocortical tumors. In the imprinted 11p15 region, the p57^KIP2 gene is maternally expressed and encodes a cyclin-dependent kinase (CDK) inhibitor involved in G₁/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 gene overexpression (mainly malignant)], and the human adrenocortical tumor cell 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 similar to that in normal adrenal tissues, as were kinase activities of G1 cyclin-CDK complexes. By contrast, abrogation of the p57^KIP2 gene expression 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 malignant 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 paternal allele or pathological functional imprinting of the 11p15 region are responsible for loss of expression of the p57^KIP2 gene and increased expression of the IGF-II gene. Consequently, both events favor cell proliferation in malignant adrenocortical tumors.

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