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Ribonucleic Acid Expression of the Clustered Imprinted Genes, p57^KIP2, Insulin-Like Growth Factor II, and H19, in Adrenal Tumors and Cultured Adrenal Cells¹

Department of Pathology, University of Helsinki (J.L., A.I.K., P.H., R.V.), FIN-00014 Helsinki; and the Department of Pediatrics, Kuopio University Hospital (R.V.), FIN-70210 Kuopio, Finland

Address all correspondence and requests for reprints to: Dr. Raimo Voutilainen, Department of Pathology, P.O. Box 21, University of Helsinki, FIN-00014 Helsinki, Finland. E-mail: Raimo.Voutilainen{at}uku.fi

The recently cloned cyclin-dependent kinase inhibitor gene p57^KIP2 is genomically imprinted and located on human chromosome 11p15.5. This region contains two other imprinted genes, insulin-like growth factor II (IGF-II) and H19, both of which seem to be implicated in adrenal neoplasms. We analyzed the expression of the putative tumor suppressor p57^KIP2 gene by Northern blotting in normal and hyperplastic adrenals, adrenocortical tumors, and pheochromocytomas. The expression of p57^KIP2 messenger ribonucleic acid (mRNA) correlated positively with H19 and negatively with IGF-II RNA in adrenocortical tissues. p57^KIP2 mRNA (and H19 RNA) was abundantly expressed in normal human adrenals, adrenocortical adenomas from patients with Cushing’s or Conn’s syndrome or without clinical evidence of hormone overproduction, hyperplastic adrenals, and tumor-adjacent adrenal tissues, in which IGF-II mRNA expression was low. In most adrenocortical carcinomas and virilizing adrenal adenomas, very low levels of both p57^KIP2 and H19 RNAs were observed, whereas IGF-II was highly expressed. In pheochromocytomas, p57^KIP2 and H19 RNA expression was highly variable, but on the average it was about 45% and 27%, respectively, of that in normal and tumor-adjacent adrenals.

In cultured adrenocortical cells, ACTH and dibutyryl cAMP treatment slightly reduced the predominant 1.7-kilobase (kb) transcript of p57^KIP2 gene, but induced a 2.5-kb transcript with a simultaneous increase in H19 RNA expression. The stimulatory effect of ACTH on the 2.5-kb p57^KIP2 and H19 transcript accumulation was enhanced by exogenous IGF-II and IGF-I. Our data show that p57^KIP2 and H19 RNAs are expressed usually in parallel in normal and pathological adrenocortical tissues. The decreased expression of both p57^KIP2 and H19 RNAs in conjunction with elevated IGF-II mRNA expression in hormonally active adrenocortical carcinomas suggests that the loss of expression of the putative tumor suppressor genes p57^KIP2 and H19 may be involved in the pathogenesis of these neoplasms.

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