Endocrine Pathology

, Volume 10, Issue 1, pp 73–83 | Cite as

Retinoid X receptors (RXRs) mRNA expression in human pituitary adenomas

  • N. Sanno
  • A. Sugawara
  • S. Tahara
  • R. Y. Osamura
  • A. Teramoto
Clinical Research


Retinoid-X receptors (RXRs) are transcriptional factors that belong to the steroid/thyroid hormone receptor (TR) superfamily. It has been demonstrated that those nuclear receptors act as ligand-activated transcription factors in pituitary cells. To determine whether RXRs play roles in the cell differentiation of pituitary adenomas, we have investigated the expression of RXRγ mRNA in various types of pituitary adenomas usingin situ reverse transcriptase-polymerase chain reaction (RT-PCR). The synergistic function on promoters of specific hormones between these nuclear receptors and pituitary specific transcription factor, Pit-1, has been noticed in in vitro experiments. The colocalization between RXRγ mRNA and Pit-1 protein was examined by combinedin situ RT-PCR and immunohistochemistry. RXRγ mRNA was detected in normal pituitary gland as well as all five growth hormone-(GH)-secreting adenomas and five thyroid stimulating hormone (TSH) secreting adenomas, two of four prolactin- (PRL) secreting adenomas, one of two adrenocorticotropin-(ACTH) secreting adenomas, one of four nonfunctioning adenomas. Byin situ hybridization andin situ RT-PCR followed by immunohistochemistry, the colocalization of Pit-1 mRNA with RXRγ as well as RXRγ mRNA with Pit-1 was observed in adenoma cells of GH-secreting adenomas and TSH-secreting adenomas. We suggest that RXRγ may play a role in cell differentiation and hormonal transcription synergistically with Pit-1 in normal and neoplastic human pituitaries.

Key Words

Retinoid nuclear receptor pituitary neoplasm mRNA in situ RT-PCR 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mangeldorf DJ, Ong ES, Dyck JA, Evans RM. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345:224–229, 1990.CrossRefGoogle Scholar
  2. 2.
    Yu VC, Delsert C, Andersen B, Holloway JM, Devary OV, Naar AM, Kim SY, Boutin JM. RXRβ: a coregulator that enhances binding of retinoic acid, thyroid hormone and vitamin D receptors to their cognate response elements. Cell 67:1251–1266, 1991.PubMedCrossRefGoogle Scholar
  3. 3.
    Leid M, Kastner P, Lyons R. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell 68:377–395, 1992.PubMedCrossRefGoogle Scholar
  4. 4.
    Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signaling. Nature 355: 446–449, 1992.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang X-K, Hoffmann B, Tran PB-V, Graupner G, Pfahl M. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature 355:441–446, 1992.PubMedCrossRefGoogle Scholar
  6. 6.
    Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, et al. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 6:329–344, 1992.PubMedCrossRefGoogle Scholar
  7. 7.
    Allenby G, Bocquel MT, Saunders M, et al. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA 90:30–34, 1993.PubMedCrossRefGoogle Scholar
  8. 8.
    Davis KD, Berrodin TJ, Stelmach JE, Winkler JD, Lazar MA. Endogenous retinoid X receptors can function as hormone receptors in pituitary cells. Mol Cel Biol 14:7105–7110, 1994.Google Scholar
  9. 9.
    Lala DS, Mukherjee R, Schulman M. Activation of specific RXR heterodimers by an antagonist of RXR homodimers. Nature 383:450–453, 1996.PubMedCrossRefGoogle Scholar
  10. 10.
    Levine AA, Sturzenbecker LJ, Kazmer S, Bosalowski T, Huselton C, Allenby G, et al. 9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα. Nature 355:359–361, 1992.CrossRefGoogle Scholar
  11. 11.
    Sugawara A, Yen PM, Chin WW. 9-cis retinoic acid regulation of rat growth hormone gene expression: potential roles of multiple nuclear hormone receptors. Endocrinol 135:1956–1962, 1994.CrossRefGoogle Scholar
  12. 12.
    Sugawara A, Yen PM, Darling DS, Chin WW. Characterization and tissue expression of multiple triiodothyronine receptor-auxiliary proteins and their relationship to the retinoid X-receptors. Endocrinology 133:965–971, 1993.PubMedCrossRefGoogle Scholar
  13. 13.
    Sugawara A, Yen PM, Qi Y, Lechan RM, Chin WW. Isoform-specific retinoid-X receptor (RXR) antibodies detect differential expression of RXR proteins in the pituitary gland. Endocrinology 136:1766–1774, 1995.PubMedCrossRefGoogle Scholar
  14. 14.
    Sanno N, Sugawara A, Teramoto A, Abe Y, Yen PM, Chin WW, et al. Immunohistochemical expression of retinoid X receptor isoforms in human pituitaries and pituitary adenomas. Neuro-endocrinology 65:299–306, 1997.Google Scholar
  15. 15.
    Bodner M, Castrillo J-L, Theill LE, Deerinck T, Ellisman M, Karin M. The pituitary-specific transcription factor GHF-1 is a homeobox-containing protein. Cell 55:505–518, 1988.PubMedCrossRefGoogle Scholar
  16. 16.
    Ingraham HA, Chen R, Mangalam HJ. A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell 55:519–529, 1988.PubMedCrossRefGoogle Scholar
  17. 17.
    Rhodes SJ, Chen R, DiMattia GE, Scully KM, Kalla KA, Lin SC, et al. A tissue-specific enhancer confers P1T-1 dependent morphogen inducibility and autoregulation on the PIT-1 gene. Genes Dev 7:913–932, 1993.PubMedCrossRefGoogle Scholar
  18. 17a.
    Steinfelder HJ, Rodovick S, Meoyuski MA. Role of a pituitary specific transcription factor (Pit-1/GHF-1) or a closely related protein in cAMP regulation of human thyrotropin-beta subunit gene expression. J Clin Invest 89:409–419, 1992.PubMedCrossRefGoogle Scholar
  19. 18.
    Schaufele F, West BL, Baxter JD. Synergistic activation of the rat growth hormone promoter by Pit-1 and the thyroid hormone receptor. Mol Endocrinol 6:656–665, 1992.PubMedCrossRefGoogle Scholar
  20. 19.
    Sanchez-Pacheco A, Palomino T, Aranda A. Retinoid acid induces expression of the transcription factor GHF-1/Pit-1 in pituitary prolactin-and growth hormone-producing cell lines. Endocrinology 136:5391–5398, 1995.PubMedCrossRefGoogle Scholar
  21. 20.
    Day RN, Koike S, Sakai M, Muramatsu M, Maurer RA. Both Pit-1 and the estrogen receptor are required for estrogen responsiveness of the rat prolactin gene. Mol Endocrinol 4:1964–1971, 1990.PubMedCrossRefGoogle Scholar
  22. 21.
    Lloyd RV, Jin L, Chandler WF. Pituitary specific transcription factor messenger ribonucleic expression in adenomatous and nontumorous human pituitary tissues. Lab Invest 69:570–575, 1993.PubMedGoogle Scholar
  23. 22.
    Sanno N, Teramoto A, Matsuno A, Itoh J, Takekoshi S, Osamura RY.In situ hybridization analysis of Pit-1 mRNA and hormonal production in human pituitary adenomas. Acta Neuropathol 91:263–268, 1996.PubMedCrossRefGoogle Scholar
  24. 23.
    Jin L, Qian X, Lloyd RV. Comparison of mRNA expression detected byin situ PCR andin situ hybridization in endocrine cells. Cell Vision 2:314–321, 1995.Google Scholar
  25. 24.
    Sanno N, Teramoto A, Matsuno A, Takekoshi S, Itoh J, Osamura RY. Expression of Pit-1 and estrogen receptor messenger ribonucleic acids in prolactin producing pituitary adenomas: non-radioisotopicin situ hybridization analysis. Mod Pathol 9:526–533, 1996.PubMedGoogle Scholar
  26. 25.
    Sanno N, Jin L, Oian X, Osamura RY, Scheithauer BW, Kovacs K, et al. Gonadotropin releasing hormone mRNA and gonadotropin releasing hormone receptor mRNA expression in pituitaries and pituitary adenomas. J Clin Endocrinol Metab 82:1974–1982, 1997.PubMedCrossRefGoogle Scholar
  27. 26.
    Sanno N, Teramoto A, Osamura RY, Genka S, Katakami H, Jin L, et al. A growth hormone-releasing hormone-producing pancreatic islet cell tumor metastasized to the pituitary is associated with pituitary somatotroph hyperplasia and acromegaly. J Clin Endocrinol Metab 82:2731–2737, 1997.PubMedCrossRefGoogle Scholar
  28. 27.
    Liu Q, Linney E. The mouse retinoid-X receptor g gene: genomic organization and evidence for functional isoforms. Mol Endocrinol 7:651–658, 1993.PubMedCrossRefGoogle Scholar
  29. 28.
    Garcia-Villalba P, Au-Fliegner M, Samuel HH, Aranda A. Interaction of thyroid hormone and retinoic acid receptors on the regulation of the rat growth gene promoter. Biochem Biophys Res Comun 191:580–586, 1993.CrossRefGoogle Scholar
  30. 29.
    Guiguere V. Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling. Endocr Rev 15:61–79, 1994.CrossRefGoogle Scholar
  31. 30.
    Yen PM, Sugawara A, Chin WW. Triiodothyronine (T3) differentially affects T3-receptor/ retinoic acid receptor and T3-receptor/retinoid X receptor heterodimer binding to DNA. J Biol Chem 267:23,248–23,252, 1992.Google Scholar
  32. 31.
    Keller H, Givel F, Perroud M, Wahli W. Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements. Mol Endocrinol 9:794–804, 1995.PubMedCrossRefGoogle Scholar
  33. 32.
    Djakoure C, Guibourdenche J, Porquet D, Pagesy P, Peillon F, Li JY, et al. Vitamin A and retinoic acid stimulate within minutes cAMP release and growth hormone secretion in human pituitary cells. J Clin Endocrinol Metab 81:3123–3125, 1996.PubMedCrossRefGoogle Scholar
  34. 33.
    Perez P, Shonthal A, Aranda A. Repression of c-fos gene expression by thyroid hormone and retinoic acid receptors. J Biol Chem 268:23,538–23,543, 1993.Google Scholar
  35. 34.
    Chuang FM, West BL, Baxter JD, Schaufele F. Activities in Pit-1 determine whether receptor interacting protein 140 activates or inhibits Pit-1/nuclear receptor transcriptional synergy. Mol Endocrinol 11:1332–1341, 1997.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1999

Authors and Affiliations

  • N. Sanno
    • 1
  • A. Sugawara
    • 2
  • S. Tahara
    • 1
  • R. Y. Osamura
    • 3
  • A. Teramoto
    • 1
  1. 1.Department of NeurosurgeryNippon Medical SchoolTokyoJapan
  2. 2.The 2nd Department of Internal Medicine, TohokuUniversity School of MedicineSendaiJapan
  3. 3.Department of PathologyTokai University School of MedicineIseharaJapan

Personalised recommendations