Skip to main content

Advertisement

SpringerLink
Log in

Reciprocal Changes in the Expression of Transcription Factors GATA-4 and GATA-6 Accompany Adrenocortical Tumorigenesis in Mice and Humans

  • Original Articles
  • Published:
Molecular Medicine Aims and scope Submit manuscript

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 α/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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D. (1994) High frequency of germline p53 mutations in childhood adrenocortical cancer. J. Natl. Cancer Inst. 86: 1707–1710.

    Article  CAS  Google Scholar 

  2. Cutler SJ, Young JL (eds). (1975) Biometrics Branch, National Cancer Institute, Third National Cancer Survey: incidence data. National Cancer Institute Monograph 41. Government Printing Office, Washington, D.C..

    Google Scholar 

  3. Sabbaga CC, Avilla SG, Schulz C, Garbers JC, Blucher D. (1994) Adrenocortical carcinoma in children: clinical aspects and prognosis. J. Pediatr. Surg. 28: 841–843.

    Article  Google Scholar 

  4. Boscaro M, Fallo F, Barzon L, Daniele O, Sonino N. (1995) Adrenocortical carcinoma: epidemiology and natural history. Minerva Endocrinol. 20: 89–94.

    CAS  PubMed  Google Scholar 

  5. Haak HR, Hermans J, van de Velde CJ, et al. (1994) Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Brit. J. Cancer 69: 947–951.

    Article  CAS  Google Scholar 

  6. Favia G, Lumachi F, Carraro P, D’Amico DF. (1995) Adrenocortical carcinoma. Our experience. Minerva Endocrinol. 20: 95–99.

    CAS  PubMed  Google Scholar 

  7. Dogliotti L, Berruti A, Pia A, Paccotti P, Ali A, Angeli A. (1995) Cytotoxic chemotherapy for adrenocortical carcinoma. Minerva Endocrinol. 20: 105–109.

    CAS  PubMed  Google Scholar 

  8. Kasperlik-Zaluska AA, Migdalska BM, Zgliczynski S, Makowska AM. (1995) Adrenocortical carcinoma. A clinical study and treatment results of 52 patients. Cancer 75: 2587–2591.

    Article  CAS  Google Scholar 

  9. Beuschlein F, Reincke M, Karl M, et al. (1994) Clonal composition of human adrenocortical neoplasms. Cancer Res. 54: 4927–4932.

    CAS  PubMed  Google Scholar 

  10. Li FP, Fraumeni Jr JF, Mulvihill JJ, et al. (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res. 48: 5358–5362.

    CAS  PubMed  Google Scholar 

  11. Wiedemann HR. (1983) Tumours and hemihy-pertrophy associated with Wiedeman-Beckwith syndrome. Eur. J. Pediatr. 141: 129.

    Article  Google Scholar 

  12. Birch JM, Hartley AL, Tricker KJ, et al. (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 54: 1298–1304.

    CAS  PubMed  Google Scholar 

  13. Miyamoto H, Kubota Y, Shuin T, Shiozaki H. (1996) Bilateral adrenocortical carcinoma showing loss of heterozygosity at the p53 and RB gene loci. Cancer Genet. Cytogenet. 88: 181–183.

    Article  CAS  Google Scholar 

  14. Hatada I, Ohashi H, Fukushima Y, et al. (1996) An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat. Genet. 14: 171–173.

    Article  CAS  Google Scholar 

  15. Skogseid B, Larsson C, Lindgren P-G, et al. (1992) Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J. Clin. Endocrinol. Metab. 75: 76–81.

    CAS  PubMed  Google Scholar 

  16. Haak HR, Fleuren GJ. (1995) Neuroendocrine differentiation of adrenocortical tumors. Cancer 75: 860–864.

    Article  CAS  Google Scholar 

  17. Kananen K, Markkula M, Rainio E, Su J-GJ, Hsueh AJW, Huhtaniemi IT. (1995) Gonadal tumorigenesis in transgenic mice bearing the mouse inhibin α-subunit promoter/Simian virus T-antigen fusion gene: characterization of ovarian tumors and establishment of gonadotropin-responsive granulosa cell lines. Mol. Endocrinol. 9: 616–627.

    CAS  PubMed  Google Scholar 

  18. Kananen K, Markkula M, el Hefnawy T, et al. (1996) The mouse inhibin α-subunit promoter directs SV40 T-antigen to Leydig cells in transgenic mice. Mol. Cell. Endocrinol. 119: 135–146.

    Article  CAS  Google Scholar 

  19. Rahman NA, Kananen K, Rilianawati X, et al. (1998) Transgenic mouse models for gonadal tumorigenesis. Mol. Cell. Endocrinol. 145: 167–174.

    Article  CAS  Google Scholar 

  20. Kananen K, Markkula M, Mikola M, Rainio E-M, McNeilly A, Huhtaniemi I. (1996) Gonadectomy permits adrenocortical tumorigenesis in mice transgenic for the mouse inhibin α-subunit promoter/Simian virus T-antigen fusion gene: evidence for negative autoregulation of the inhibin α-subunit gene. Mol. Endocrinol. 10: 1667–1677.

    CAS  PubMed  Google Scholar 

  21. Kananen K, Rilianawati X, Paukku T, Markkula M, Rainio E-M, Huhtaniemi I. (1997) Suppression of gonadotropins inhibits gonadal tumorigenesis in mice transgenic for the mouse inhibin α-subunit promoter/Simian virus T-antigen fusion gene. Endocrinology 138: 3521–3531.

    Article  CAS  Google Scholar 

  22. Rilianawati X, Paukku T, Kero J, et al. (1998) Direct luteinizing hormone action triggers adrenocortical tumorigenesis in castrated mice transgenic for the murine inhibin α-subunit promoter/Simian virus 40 T-antigen fusion gene. Mol. Endocrinol. 12: 801–809.

    CAS  PubMed  Google Scholar 

  23. deLange WE, Pratt JJ, Doorenbos H. (1980) A gonadotropin-responsive testosterone producing adrenocortical adenoma and high gonadotropin levels in an elderly woman. Clin. Endocrinol. 12: 21–28.

    Article  CAS  Google Scholar 

  24. Leinonen P, Ranta T, Siegberg R, Heikkilä P, Kahri A. (1991) Testosterone secreting virilizing adrenal adenoma with human chorionic gonatropin receptors and 21-hydroxylase deficiency. Clin. Endocrinol. 34: 31–35.

    Article  CAS  Google Scholar 

  25. Orkin SH. (1992) GATA-binding transcription factors in hematopoietic cells. Blood 80: 575–581.

    CAS  PubMed  Google Scholar 

  26. Evans T. (1997) Regulation of cardiac gene expression by GATA-4/5/6. Trends Card. Med. 7: 75–83.

    Article  CAS  Google Scholar 

  27. Arceci RJ, King AAJ, Simon MC, Orkin SH, Wilson DB. (1993) Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermal derivatives and heart. Mol. Cell Biol. 13: 2235–2246.

    Article  CAS  Google Scholar 

  28. Laverriere AC, MacNeill C, Mueller C, Poelman RE, Burch JBE, Evans T. (1994) GATA4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut. J. Biol. Chem. 269: 23177–23184.

    CAS  PubMed  Google Scholar 

  29. Narita N, Heikinheimo M, Bielinska M, White RA, Wilson DB. (1996) The gene for transcription factor GATA-6 resides on mouse chromosome 18 and is expressed in myocardium and vascular smooth muscle. Genomics 36: 345–348.

    Article  CAS  Google Scholar 

  30. Morrisey EE, Ip HS, Lu MM, Parmacek MS. (1996) GATA-6: a zinc finger transcription factor that is derived from lateral mesoderm. Dev. Biol. 177: 309–322.

    Article  CAS  Google Scholar 

  31. Heikinheimo M, Ermolaeva M, Bielinska M, et al. (1997) Expression and hormonal regulation of transcription factors GATA-4 and GATA-6 in the mouse ovary. Endocrinology 138: 3505–3514.

    Article  CAS  Google Scholar 

  32. Viger RS, Mertineit C, Trasler JM, Nemer M. (1998) Transcription factor GATA-4 is expressed in asexually dimorphic pattern during mouse gonadal development and is a potent activator of the Müllerian inhibiting substance. Development 125: 2665–2675.

    CAS  PubMed  Google Scholar 

  33. Ketola I, Rahman N, Toppari J, et al. (1999) Expression and regulation of transcription factors GATA-4 and GATA-6 in developing mouse testis. Endocrinology 140: 1470–1480.

    Article  CAS  Google Scholar 

  34. Lawson MA, Mellon PL. (1998) Expression of GATA-4 in migrating gonadotropin-releasing neurons of the developing mouse. Mol. Cell. Endocrin. 140: 157–161.

    Article  CAS  Google Scholar 

  35. Lawson MA, Buhain AR, Jovenal JC, Mellon PL. (1998) Multiple factors interacting with GATA sites of the gonadotropin releasing hormone neuron specific enhancer regulate gene expression. Mol. Endocrin. 12: 364–377.

    Article  CAS  Google Scholar 

  36. Parker KL, Schimmer BP. (1997) Steroidogenic factor 1: a key determinant of endocrine development and function. Endocrin. Rev. 18: 361–377.

    Article  CAS  Google Scholar 

  37. Kaufman MH. (1992) The Atlas of Mouse Development. London: Academic Press.

    Google Scholar 

  38. Wilkinson DG. (1992) Whole mount in situ hybridization of vertebrate embryos. In: Wilkinson DG (ed), In situ Hybridization—A Practical Approach. IRL Press, Oxford, pp. 75–83.

    Google Scholar 

  39. Heikinheimo M, Scandrett J, Wilson DB. (1994) Localization of transcription factor GATA-4 to regions of mouse embryo involved in cardiac development. Dev. Biol. 164: 361–373.

    Article  CAS  Google Scholar 

  40. Efrat S, Hanahan D. (1987) Bidirectional activity of the rat insulin II 5′ flanking region in transgenic mice. Mol. Cell. Biol. 7: 192–198.

    Article  CAS  Google Scholar 

  41. Richards JS. (1994) Hormonal control of gene expression in the ovary. Endocrin. Rev. 15: 725–751.

    Article  CAS  Google Scholar 

  42. Yomodiga K, Ohtani H, Harigae H, et al. (1994) Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells. Development 120: 1759–1766.

    Google Scholar 

  43. Grépin C, Dagnino L, Robitaille L, Haberstroh L, Antakly T, Nemer M. (1994) A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription. Mol. Cell. Biol. 14: 3115–3129.

    Article  Google Scholar 

  44. Lawson MA, Whyte DB, Mellon PL. (1996) GATA factors are essential for activity of the neuron-specific enhancer of the gonadotropin-releasing hormone gene. Mol. Cell. Biol. 16: 3596–3605.

    Article  CAS  Google Scholar 

  45. Kuo CT, Morrisey EE, Anandappa R, et al. (1997) GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 11: 1048–1060.

    Article  CAS  Google Scholar 

  46. Molkentin JD, Lin Q, Duncan SA, Olson EN. (1997) Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 11: 1061–1072.

    Article  CAS  Google Scholar 

  47. Morrisey EE, Tang Z, Sigrist K, et al. (1998) GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 12: 3579–3590.

    Article  CAS  Google Scholar 

  48. Bielinska M, Wilson DB. (1997) Introduction of yolk sac endoderm in GATA-4 deficient embryoid bodies by retinoic acid. Mech. Devel. 65: 43–54.

    Article  CAS  Google Scholar 

  49. Sasano H, Shizawa S, Nagura H. (1995) Adrenocortical cytopathology. Am. J. Clin. Pathol. 104: 161–166.

    Article  CAS  Google Scholar 

  50. Sharma S, Singh R, Verma K. (1997) Cytomorphology of adrenocortical carcinoma and comparison with renal cell carcinoma. Acta Cytol. 41: 385–392.

    Article  CAS  Google Scholar 

  51. Chan JK, Tsang WY. (1995) Endocrine malignancies that may mimic benign lesions. Semin. Diagn. Pathol. 12: 45–63.

    CAS  PubMed  Google Scholar 

  52. Tartour E, Caillou B, Tenenbaum F, et al. (1993) Immunohistochemical study of adrenocortical carcinoma. Predictive value of the D11 monoclonal antibody. Cancer 72: 3296–3303.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Juselius Foundation (ITH, DBW, and MH), the Finnish Cancer Foundation (ITH), the Finnish Pediatric Foundation (MH), the University Central Hospital in Helsinki (SK, SS, and MH), the NIH (LJM), a Burroughs Wellcome Fund Career Development Award (LJM), Pediatric Cardiology SCOR HL61006 (DBW), the Washington University Monsanto-Searle Agreement (DBW), and an Established Investigator Award from the AHA (DBW).

Author information

Authors and Affiliations

  1. Children’s Hospital, University of Helsinki, Stenbäckinkatu 11, 00290, Helsinki, Finland

    Sanne Kiiveri, Susanna Siltanen &  Markku Heikinheimo

  2. Department of Physiology, University of Turku, Turku, Finland

    Nafis Rahman & Ilpo T. Huhtaniemi

  3. Department of Pediatrics, Washington University, St. Louis, Missouri, USA

    Malgorzata Bielinska, Louis J. Muglia, David B. Wilson &  Markku Heikinheimo

  4. Department of Pathology, University of Oulu, Oulu, Finland

    Veli-Pekka Lehto

  5. Department of Molecular Biology and Pharmacology, Washington University, St. Louis, Missouri, USA

    Louis J. Muglia & David B. Wilson

Authors
  1. Sanne Kiiveri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susanna Siltanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nafis Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Malgorzata Bielinska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Veli-Pekka Lehto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ilpo T. Huhtaniemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Louis J. Muglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David B. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Markku Heikinheimo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markku Heikinheimo.

Additional information

This work was performed at Children’s Hospital, University of Helsinki and Department of Pediatrics, Washington University of St. Louis. S. Kiiveri and S. Siltanen contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kiiveri, S., Siltanen, S., Rahman, N. et al. Reciprocal Changes in the Expression of Transcription Factors GATA-4 and GATA-6 Accompany Adrenocortical Tumorigenesis in Mice and Humans. Mol Med 5, 490–501 (1999). https://doi.org/10.1007/BF03403542

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03403542

Search

Navigation