This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, J. Articles by Voutilainen, R. Search for Related Content PubMed PubMed Citation Articles by Liu, J. Articles by Voutilainen, R.

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.

This article has been cited by other articles:

				P. Pigny, A. Vincent, C. Cardot Bauters, M. Bertrand, V. T. de Montpreville, M. Crepin, N. Porchet, and P. Caron Paraganglioma after Maternal Transmission of a Succinate Dehydrogenase Gene Mutation J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1609 - 1615. [Abstract] [Full Text] [PDF]

				R. Libe, A. Fratticci, and J. Bertherat Adrenocortical cancer: pathophysiology and clinical management Endocr. Relat. Cancer, March 1, 2007; 14(1): 13 - 28. [Abstract] [Full Text] [PDF]

				H. Kobayashi, F. Kambe, T. Imai, Y. Hibi, T. Kikumori, S. Ohmori, A. Nakao, and H. Seo Differential expression of cyclin-dependent kinase inhibitors, p27Kip1 and p57Kip2, by corticotropin in rat adrenal cortex. J. Endocrinol., June 1, 2006; 189(3): 671 - 679. [Abstract] [Full Text] [PDF]

				B. Ragazzon, A.-M. Lefrancois-Martinez, P. Val, I. Sahut-Barnola, C. Tournaire, C. Chambon, J.-L. Gachancard-Bouya, R.-J. Begue, G. Veyssiere, and A. Martinez Adrenocorticotropin-Dependent Changes in SF-1/DAX-1 Ratio Influence Steroidogenic Genes Expression in a Novel Model of Glucocorticoid-Producing Adrenocortical Cell Lines Derived from Targeted Tumorigenesis Endocrinology, April 1, 2006; 147(4): 1805 - 1818. [Abstract] [Full Text] [PDF]

				R. Libe and J. Bertherat Molecular genetics of adrenocortical tumours, from familial to sporadic diseases Eur. J. Endocrinol., October 1, 2005; 153(4): 477 - 487. [Abstract] [Full Text] [PDF]

				C D E Margetts, D Astuti, D C Gentle, W N Cooper, A Cascon, D Catchpoole, M Robledo, H P H Neumann, F Latif, and E R Maher Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas Endocr. Relat. Cancer, March 1, 2005; 12(1): 161 - 172. [Abstract] [Full Text] [PDF]

				J Liu, X-D Li, A Vaheri, and R Voutilainen DNA methylation affects cell proliferation, cortisol secretion and steroidogenic gene expression in human adrenocortical NCI-H295R cells J. Mol. Endocrinol., December 1, 2004; 33(3): 651 - 662. [Abstract] [Full Text] [PDF]

				A.-M. Lefrancois-Martinez, J. Bertherat, P. Val, C. Tournaire, N. Gallo-Payet, D. Hyndman, G. Veyssiere, X. Bertagna, C. Jean, and A. Martinez Decreased Expression of Cyclic Adenosine Monophosphate-Regulated Aldose Reductase (AKR1B1) Is Associated with Malignancy in Human Sporadic Adrenocortical Tumors J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3010 - 3019. [Abstract] [Full Text] [PDF]

				C. A. Koch, K. Pacak, and G. P. Chrousos The Molecular Pathogenesis of Hereditary and Sporadic Adrenocortical and Adrenomedullary Tumors J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5367 - 5384. [Abstract] [Full Text] [PDF]

				N. Kanayama, K. Takahashi, T. Matsuura, M. Sugimura, T. Kobayashi, N. Moniwa, M. Tomita, and K. Nakayama Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice Mol. Hum. Reprod., December 1, 2002; 8(12): 1129 - 1135. [Abstract] [Full Text] [PDF]

				Z.-H. Gao, S. Suppola, J. Liu, P. Heikkila, J. Janne, and R. Voutilainen Association of H19 Promoter Methylation with the Expression of H19 and IGF-II Genes in Adrenocortical Tumors J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1170 - 1176. [Abstract] [Full Text] [PDF]

				C. Gicquel, X. Bertagna, V. Gaston, J. Coste, A. Louvel, E. Baudin, J. Bertherat, Y. Chapuis, J.-M. Duclos, M. Schlumberger, et al. Molecular Markers and Long-Term Recurrences in a Large Cohort of Patients with Sporadic Adrenocortical Tumors Cancer Res., September 1, 2001; 61(18): 6762 - 6767. [Abstract] [Full Text] [PDF]

				F. Wilkin, N. Gagné, J. Paquette, L. L. Oligny, and C. Deal Pediatric Adrenocortical Tumors: Molecular Events Leading to Insulin-Like Growth Factor II Gene Overexpression J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2048 - 2056. [Abstract] [Full Text]

				A. Hoeflich, O. Fettscher, H. Lahm, W. F. Blum, H. J. Kolb, D. Engelhardt, E. Wolf, and M. M. Weber Overexpression of Insulin-like Growth Factor-binding Protein-2 Results in Increased Tumorigenic Potential in Y-1 Adrenocortical Tumor Cells Cancer Res., February 1, 2000; 60(4): 834 - 838. [Abstract] [Full Text]

				N. Bourcigaux, V. Gaston, A. Logié, X. Bertagna, Y. Le Bouc, and C. Gicquel High Expression of Cyclin E and G1 CDK and Loss of Function of p57KIP2 Are Involved in Proliferation of Malignant Sporadic Adrenocortical Tumors J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 322 - 330. [Abstract] [Full Text]

				M. K. R. Samuelsson, A. Pazirandeh, B. Davani, and S. Okret p57Kip2, a Glucocorticoid-Induced Inhibitor of Cell Cycle Progression in HeLa Cells Mol. Endocrinol., November 1, 1999; 13(11): 1811 - 1822. [Abstract] [Full Text]

				R. G. Pestell, C. Albanese, A. T. Reutens, J. E. Segall, R. J. Lee, and A. Arnold The Cyclins and Cyclin-Dependent Kinase Inhibitors in Hormonal Regulation of Proliferation and Differentiation Endocr. Rev., August 1, 1999; 20(4): 501 - 534. [Abstract] [Full Text] [PDF]

				S. R. Bornstein, C. A. Stratakis, and G. P. Chrousos Adrenocortical Tumors: Recent Advances in Basic Concepts and Clinical Management Ann Intern Med, May 4, 1999; 130(9): 759 - 771. [Abstract] [Full Text] [PDF]

				B. C. Figueiredo, C. A. Stratakis, R. Sandrini, L. DeLacerda, M. A. D. Pianovsky, C. Giatzakis, H. M. Young, and B. R. Haddad Comparative Genomic Hybridization Analysis of Adrenocortical Tumors of Childhood J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1116 - 1121. [Abstract] [Full Text]

				R. V. Lloyd, L. A. Erickson, L. Jin, E. Kulig, X. Qian, J. C. Cheville, and B. W. Scheithauer p27kip1: A Multifunctional Cyclin-Dependent Kinase Inhibitor with Prognostic Significance in Human Cancers Am. J. Pathol., February 1, 1999; 154(2): 313 - 323. [Abstract] [Full Text] [PDF]