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Mol Med. Jul 1999; 5(7): 490–501.
PMCID: PMC2230442

Reciprocal changes in the expression of transcription factors GATA-4 and GATA-6 accompany adrenocortical tumorigenesis in mice and humans.

Abstract

While certain genetic changes are frequently found in adrenocortical carcinoma cells, the molecular basis of adrenocortical tumorigenesis remains poorly understood. Given that the transcription factors GATA-4 and GATA-6 have been implicated in gene expression and cellular differentiation in a variety of tissues, including endocrine organs such as testis, we have now examined their expression in the developing adrenal gland, as well as in adrenocortical cell lines and tumors from mice and humans. Northern blot analysis and in situ hybridization revealed abundant GATA-6 mRNA in the fetal and postnatal adrenal cortex of the mouse. In contrast, little or no GATA-4 expression was detected in adrenal tissue during normal development. In vivo stimulation with ACTH or suppression with dexamethasone did not affect the expression of GATA-4 or GATA-6 in the murine adrenal gland. To assess whether changes in the expression of GATA-4 or GATA-6 accompany adrenocortical tumorigenesis, we employed an established mouse model. When gonadectomized, inhibin alpha/SV40 T-antigen transgenic mice develop adrenocortical tumors in a gonadotropin-dependent fashion. In striking contrast to the normal adrenal glands, GATA-6 mRNA was absent from adrenocortical tumors or tumor-derived cell lines, while GATA-4 mRNA and protein were abundantly expressed in the tumors and tumor cell lines. Analogous results were obtained with human tissue samples; GATA-4 expression was detected in human adrenocortical carcinomas but not in normal tissue, adenomas, or pheochromocytomas. Taken together these results suggest different roles for GATA-4 and GATA-6 in the adrenal gland, and implicate GATA-4 in adrenal tumorigenesis. Immunohistochemical detection of GATA-4 may serve as a useful marker in the differential diagnosis of human adrenal tumors.

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  • Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D. High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst. 1994 Nov 16;86(22):1707–1710. [PubMed]
  • Sabbaga CC, Avilla SG, Schulz C, Garbers JC, Blucher D. Adrenocortical carcinoma in children: clinical aspects and prognosis. J Pediatr Surg. 1993 Jun;28(6):841–843. [PubMed]
  • Boscaro M, Fallo F, Barzon L, Daniele O, Sonino N. Adrenocortical carcinoma: epidemiology and natural history. Minerva Endocrinol. 1995 Mar;20(1):89–94. [PubMed]
  • Haak HR, Hermans J, van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, Krans HM. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer. 1994 May;69(5):947–951. [PMC free article] [PubMed]
  • Favia G, Lumachi F, Carraro P, D'Amico DF. Adrenocortical carcinoma. Our experience. Minerva Endocrinol. 1995 Mar;20(1):95–99. [PubMed]
  • Dogliotti L, Berruti A, Pia A, Paccotti P, Alì A, Angeli A. Cytotoxic chemotherapy for adrenocortical carcinoma. Minerva Endocrinol. 1995 Mar;20(1):105–109. [PubMed]
  • Kasperlik-Załuska AA, Migdalska BM, Zgliczyński S, Makowska AM. Adrenocortical carcinoma. A clinical study and treatment results of 52 patients. Cancer. 1995 May 15;75(10):2587–2591. [PubMed]
  • Beuschlein F, Reincke M, Karl M, Travis WD, Jaursch-Hancke C, Abdelhamid S, Chrousos GP, Allolio B. Clonal composition of human adrenocortical neoplasms. Cancer Res. 1994 Sep 15;54(18):4927–4932. [PubMed]
  • Li FP, Fraumeni JF, Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988 Sep 15;48(18):5358–5362. [PubMed]
  • Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, Harris M, Jones PH, Binchy A, Crowther D, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994 Mar 1;54(5):1298–1304. [PubMed]
  • Miyamoto H, Kubota Y, Shuin T, Shiozaki H. Bilateral adrenocortical carcinoma showing loss of heterozygosity at the p53 and RB gene loci. Cancer Genet Cytogenet. 1996 Jun;88(2):181–183. [PubMed]
  • Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, Komoto Y, Okada A, Ohishi S, Nabetani A, Morisaki H, et al. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet. 1996 Oct;14(2):171–173. [PubMed]
  • Skogseid B, Larsson C, Lindgren PG, Kvanta E, Rastad J, Theodorsson E, Wide L, Wilander E, Oberg K. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 1992 Jul;75(1):76–81. [PubMed]
  • Haak HR, Fleuren GJ. Neuroendocrine differentiation of adrenocortical tumors. Cancer. 1995 Feb 1;75(3):860–864. [PubMed]
  • Kananen K, Markkula M, Rainio E, Su JG, Hsueh AJ, Huhtaniemi IT. Gonadal tumorigenesis in transgenic mice bearing the mouse inhibin alpha-subunit promoter/simian virus T-antigen fusion gene: characterization of ovarian tumors and establishment of gonadotropin-responsive granulosa cell lines. Mol Endocrinol. 1995 May;9(5):616–627. [PubMed]
  • Kananen K, Markkula M, el-Hefnawy T, Zhang FP, Paukku T, Su JG, Hsueh AJ, Huhtaniemi I. The mouse inhibin alpha-subunit promoter directs SV40 T-antigen to Leydig cells in transgenic mice. Mol Cell Endocrinol. 1996 May 31;119(2):135–146. [PubMed]
  • Rahman NA, Kananen Rilianawati K, Paukku T, Mikola M, Markkula M, Hämäläinen T, Huhtaniemi IT. Transgenic mouse models for gonadal tumorigenesis. Mol Cell Endocrinol. 1998 Oct 25;145(1-2):167–174. [PubMed]
  • Kananen K, Markkula M, Mikola M, Rainio EM, McNeilly A, Huhtaniemi I. Gonadectomy permits adrenocortical tumorigenesis in mice transgenic for the mouse inhibin alpha-subunit promoter/simian virus 40 T-antigen fusion gene: evidence for negative autoregulation of the inhibin alpha-subunit gene. Mol Endocrinol. 1996 Dec;10(12):1667–1677. [PubMed]
  • Kananen K, Rilianawati, Paukku T, Markkula M, Rainio EM, Huhtaniemi I, Huhtanemi I. Suppression of gonadotropins inhibits gonadal tumorigenesis in mice transgenic for the mouse inhibin alpha-subunit promoter/simian virus 40 T-antigen fusion gene. Endocrinology. 1997 Aug;138(8):3521–3531. [PubMed]
  • Rilianawati, Paukku T, Kero J, Zhang FP, Rahman N, Kananen K, Huhtaniemi I. Direct luteinizing hormone action triggers adrenocortical tumorigenesis in castrated mice transgenic for the murine inhibin alpha-subunit promoter/simian virus 40 T-antigen fusion gene. Mol Endocrinol. 1998 Jun;12(6):801–809. [PubMed]
  • de Lange WE, Pratt JJ, Doorenbos H. A gonadotrophin responsive testosterone producing adrenocortical adenoma and high gonadotrophin levels in an elderly woman. Clin Endocrinol (Oxf) 1980 Jan;12(1):21–28. [PubMed]
  • Leinonen P, Ranta T, Siegberg R, Pelkonen R, Heikkilä P, Kahri A. Testosterone-secreting virilizing adrenal adenoma with human chorionic gonadotrophin receptors and 21-hydroxylase deficiency. Clin Endocrinol (Oxf) 1991 Jan;34(1):31–35. [PubMed]
  • Orkin SH. GATA-binding transcription factors in hematopoietic cells. Blood. 1992 Aug 1;80(3):575–581. [PubMed]
  • Arceci RJ, King AA, Simon MC, Orkin SH, Wilson DB. Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart. Mol Cell Biol. 1993 Apr;13(4):2235–2246. [PMC free article] [PubMed]
  • Laverriere AC, MacNeill C, Mueller C, Poelmann RE, Burch JB, Evans T. GATA-4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut. J Biol Chem. 1994 Sep 16;269(37):23177–23184. [PubMed]
  • Narita N, Heikinheimo M, Bielinska M, White RA, Wilson DB. The gene for transcription factor GATA-6 resides on mouse chromosome 18 and is expressed in myocardium and vascular smooth muscle. Genomics. 1996 Sep 1;36(2):345–348. [PubMed]
  • Morrisey EE, Ip HS, Lu MM, Parmacek MS. GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. Dev Biol. 1996 Jul 10;177(1):309–322. [PubMed]
  • Heikinheimo M, Ermolaeva M, Bielinska M, Rahman NA, Narita N, Huhtaniemi IT, Tapanainen JS, Wilson DB. Expression and hormonal regulation of transcription factors GATA-4 and GATA-6 in the mouse ovary. Endocrinology. 1997 Aug;138(8):3505–3514. [PubMed]
  • Viger RS, Mertineit C, Trasler JM, Nemer M. Transcription factor GATA-4 is expressed in a sexually dimorphic pattern during mouse gonadal development and is a potent activator of the Müllerian inhibiting substance promoter. Development. 1998 Jul;125(14):2665–2675. [PubMed]
  • Ketola I, Rahman N, Toppari J, Bielinska M, Porter-Tinge SB, Tapanainen JS, Huhtaniemi IT, Wilson DB, Heikinheimo M. Expression and regulation of transcription factors GATA-4 and GATA-6 in developing mouse testis. Endocrinology. 1999 Mar;140(3):1470–1480. [PubMed]
  • Lawson MA, Mellon PL. Expression of GATA-4 in migrating gonadotropin-releasing neurons of the developing mouse. Mol Cell Endocrinol. 1998 May 25;140(1-2):157–161. [PubMed]
  • Lawson MA, Buhain AR, Jovenal JC, Mellon PL. Multiple factors interacting at the GATA sites of the gonadotropin-releasing hormone neuron-specific enhancer regulate gene expression. Mol Endocrinol. 1998 Mar;12(3):364–377. [PubMed]
  • Parker KL, Schimmer BP. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev. 1997 Jun;18(3):361–377. [PubMed]
  • Heikinheimo M, Scandrett JM, Wilson DB. Localization of transcription factor GATA-4 to regions of the mouse embryo involved in cardiac development. Dev Biol. 1994 Aug;164(2):361–373. [PubMed]
  • Efrat S, Hanahan D. Bidirectional activity of the rat insulin II 5'-flanking region in transgenic mice. Mol Cell Biol. 1987 Jan;7(1):192–198. [PMC free article] [PubMed]
  • Richards JS. Hormonal control of gene expression in the ovary. Endocr Rev. 1994 Dec;15(6):725–751. [PubMed]
  • Ovary Z. Passive cutaneous anaphylactic reactions as tools in the study of the structure of the IgG molecule. Immunochemistry. 1978 Nov;15(10-11):751–754. [PubMed]
  • Yomogida K, Ohtani H, Harigae H, Ito E, Nishimune Y, Engel JD, Yamamoto M. Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells. Development. 1994 Jul;120(7):1759–1766. [PubMed]
  • Grépin C, Dagnino L, Robitaille L, Haberstroh L, Antakly T, Nemer M. A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription. Mol Cell Biol. 1994 May;14(5):3115–3129. [PMC free article] [PubMed]
  • Lawson MA, Whyte DB, Mellon PL. GATA factors are essential for activity of the neuron-specific enhancer of the gonadotropin-releasing hormone gene. Mol Cell Biol. 1996 Jul;16(7):3596–3605. [PMC free article] [PubMed]
  • Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C, Leiden JM. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 1997 Apr 15;11(8):1048–1060. [PubMed]
  • Molkentin JD, Lin Q, Duncan SA, Olson EN. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 1997 Apr 15;11(8):1061–1072. [PubMed]
  • Morrisey EE, Tang Z, Sigrist K, Lu MM, Jiang F, Ip HS, Parmacek MS. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 1998 Nov 15;12(22):3579–3590. [PMC free article] [PubMed]
  • Bielinska M, Wilson DB. Induction of yolk sac endoderm in GATA-4-deficient embryoid bodies by retinoic acid. Mech Dev. 1997 Jul;65(1-2):43–54. [PubMed]
  • Sasano H, Shizawa S, Nagura H. Adrenocortical cytopathology. Am J Clin Pathol. 1995 Aug;104(2):161–166. [PubMed]
  • Sharma S, Singh R, Verma K. Cytomorphology of adrenocortical carcinoma and comparison with renal cell carcinoma. Acta Cytol. 1997 Mar-Apr;41(2):385–392. [PubMed]
  • Chan JK, Tsang WY. Endocrine malignancies that may mimic benign lesions. Semin Diagn Pathol. 1995 Feb;12(1):45–63. [PubMed]
  • Tartour E, Caillou B, Tenenbaum F, Schröder S, Luciani S, Talbot M, Schlumberger M. Immunohistochemical study of adrenocortical carcinoma. Predictive value of the D11 monoclonal antibody. Cancer. 1993 Dec 1;72(11):3296–3303. [PubMed]

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