| Section on Molecular Endocrinology | |||
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RESEARCH The Section on Molecular Endocrinology studies the structure-function properties of gonadotropin and prolactin receptors, and the regulation of their expression by homologous and heterologous hormones. The hormonal control of gonadal function, including steroidogenic enzymes of the androgen pathway and novel genes regulated by gonadotropins, is also investigated. This work includes studies on the regulation of transcription of the luteninizing hormone (LH) receptor and its expression in the testis and ovary development. Current research includes studies on the mechanisms of inhibition and stimulation of transcription of the LH receptor by orphan receptors (EAR2, EAR3/COUP-TFI and TR4); the differences between species; and the modulatory changes that occur during gonadotropin-induced maturation of cultured granulosa cells and in Leydig cells at prepubertal and pubertal stages. Other studies are concerned with the regulation of the LH receptor and steroidogenic enzyme genes by gonadotropin, steroids and second messengers, or by novel genes at the transcriptional level. Recent studies utilizing differential display analysis have identified a novel gene, termed GRTH-DDX25 (Gonadotropin Regulated Testicular Helicase) that is transcriptionally regulated by gonadotopin. This gene is a member of the family of RNA helicases and is specifically expressed in Leydig cells and meiotic cells (pachytene spermatocytes). GRTH shares conserved core domains with all other members of the DEAD-box protein family of RNA helicases. Apart from its genetic closeness to mouse DBP5 protein (50% aa identity), the N-and C-terminal extensions of GRTH from the signature sequences show little similarity to other members of the family.GRTH is markedly up-regulated by hCG via cAMP-induced androgen formation in Leydig cells, at hormone concentrations that cause down-regulation of LH receptors and steroidogenic enzymes. Androgen produced by gonadotropin stimulation exerts intracrine/autocrine actions on GRTH, and could influence its transcription within the seminiferous tubule. GRTH functions as a transcriptional activator, and could contribute to the control of steroidogenesis, including the restoration of down-regulated functions. It could also mediate paracrine regulation of androgen-dependent gene(s) involved in the meiotic process, and may thus have a role in spermatogenesis. Current studies are addressing the androgen control of the GRTH gene at the transcriptional level. Also, a previously unidentified protein that is constitutively present in Leydig cells and down-regulated by gonadotropin was recently cloned and characterized as a gonadotropin-regulated long chain acyl CoA synthetase (GRLACs). This protein, which is expressed in the pubertal and adult Leydig cells of the rat testis and shares sequence indentity with two conserved regions of the LACS and luciferase families, displays low overall amino acid similarities with other members of the LACS family (23-28%). The expressed GR-LACS protein present in the cytoplasm of transfected cells displayed acyl-CoA synthetase activity for long chain fatty acid substrates. In addition to the potential contributions to energy production and testicular steoidogenesis, GR-LACS could provide long-chain acyl-CoA esters with regulatory effects on enzyme ativity, membrane function and gene expression. The function of GRTH and GR-LACS will also be analyzed by the development of a null mouse model to evaluate their roles in steroidogenesis and spermatogenesis. Research
on the prolactin receptor has focused on its molecular structure and
the regulation of its transcription. Recent studies have included
the characterization of the upstream domains that drive transcription
of the receptor gene, and the identification of several independent
promoters. These include three in the rat -- one rat and gonad-specific,
and five in the human -- four SECTION CHIEF Maria
Dufau received her M.D. and Ph.D. degrees from the National University
of Cuyo, Mendoza, Argentina. She received clinical and research training
at the Massachusetts General Hospital and Boston Lying-In Hospital,
Harvard Medical School, and New York Hospital, Cornell University.
She served an Investigator at the Clinical Research Institute of Montreal,
and as a Lecturer in Medicine, Prince Henry's Hospital, Monash University,
Melbourne, Australia. She joined the NICHD as a Visiting Scientist
in 1970 and became Head of the Section on Molecular Endocrinology,
Endocrinology and Reproduction Research Branch, NICHD in 1979. Contact Information Maria
Dufau, M.D., Ph.D
PERSONNEL ·
Jianping Meng, M.D., Bldg. 49, Rm. 6C12; tel: 301-496-5254;
email: mengj@mail.nih.gov BIBLIOGRAPHY Zhang Y, Dufau ML. (2001) EAR2 and EAR3/COUP-TFI Regulate Transcription of the Rat LH Receptor. Mol Endocrinol. 5(11):1891-905. Hu ZZ, Meng J, Dufau ML. (2001) Isolation and characterization of two novel forms of the human prolactin receptor generated by alternative splicing of a newly identified exon 11. J Biol Chem. 276(44):41086-94. Chandrashekar V, Bartke A, Awoniyi CA, Tsai-Morris CH, Dufau ML, Russell LD, Kopchick JJ. (2001) Testicular endocrine function in GH receptor gene disrupted mice. Endocrinology. 142(8):3443-50. Tang PZ, Tsai-Morris CH, Dufau ML. (2001) Cloning and characterization of a hormonally regulated rat long chain acyl-CoA synthetase. Proc Natl Acad Sci U S A. 98(12):6581-6. Dufau
ML, Tsai-Morris C, Tang P, Khanum A. (2001) Regulation
of steroidogenic enzymes and a novel testicular RNA helicase.
J Steroid Biochem Mol Biol. 76(1-5):187-97. Zhang Y, Dufau ML. (2000) Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. J Biol Chem. 275(4):2763-70. Tang PZ, Tsai-Morris CH, Dufau ML. (1999) A novel gonadotropin-regulated testicular RNA helicase. A new member of the dead-box family. J Biol Chem. 274(53):37932-40. Caprio M, Isidori AM, Carta AR, Moretti C, Dufau ML, Fabbri A. (1999) Expression of functional leptin receptors in rodent Leydig cells. Endocrinology. 140(11):4939-47. Geng Y, Tsai-Morris CH, Zhang Y, Dufau ML. (1999) The human luteinizing hormone receptor gene promoter: activation by Sp1 and Sp3 and inhibitory regulation. Biochem Biophys Res Commun. 263(2):366-71. Tsai-Morris CH, Khanum A, Tang PZ, Dufau ML. (1999) The rat 17beta-hydroxysteroid dehydrogenase type III: molecular cloning and gonadotropin regulation. Endocrinology. 140(8):3534-42. Hu ZZ, Zhuang L, Meng J, Leondires M, Dufau ML. (1999) The human prolactin receptor gene structure and alternative promoter utilization: the generic promoter hPIII and a novel human promoter hP(N). J Clin Endocrinol Metab. 84(3):1153-6 Tsai-Morris CH, Geng Y, Buczko E, Dehejia A, Dufau ML. (1999) Genomic distribution and gonadal mRNA expression of two human luteinizing hormone receptor exon 1 sequences in random populations. Hum Hered. 49(1):48-51. Tang PZ, Tsai-Morris CH, Dufau ML. (1998) Regulation of 3beta-hydroxysteroid dehydrogenase in gonadotropin-induced steroidogenic desensitization of Leydig cells. Endocrinology. 139(11):4496-505. Hu ZZ, Zhuang L, Meng J, Dufau ML. (1998) Transcriptional regulation of the generic promoter III of the rat prolactin receptor gene by C/EBPbeta and Sp1. J Biol Chem. 273(40):26225-35. Dufau ML. (1998) The luteinizing hormone receptor. Annu Rev Physiol. 60:461-96. Tsai-Morris CH, Geng Y, Buczko E, Dufau ML. (1998) A novel human luteinizing hormone receptor gene. J Clin Endocrinol Metab. 83(1):288-91. Hu Z, Zhuang L, Guan X, Meng J, Dufau ML. (1997) Steroidogenic factor-1 is an essential transcriptional activator for gonad-specific expression of promoter I of the rat prolactin receptor gene. J Biol Chem. 1997 272(22):14263-71. Khanum A, Buczko E, Dufau ML. (1997) Essential role of adenosine triphosphate in activation of 17beta-hydroxysteroid dehydrogenase in the rat Leydig cell. Endocrinology. 138(4):1612-20. Dufau ML, Miyagawa Y, Takada S, Khanum A, Miyagawa H, Buczko E. (1997) Regulation of androgen synthesis: the late steroidogenic pathway. Steroids. 62(1):128-32. Tsai-Morris CH, Buczko E, Geng Y, Gamboa-Pinto A, Dufau ML. (1996) The genomic structure of the rat corticotropin releasing factor receptor. A member of the class II G protein-coupled receptors. J Biol Chem. 271(24):14519-25. |
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