Margaret A. Shupnik, Ph.D.
Professor
Endocrinology, and 
Molecular Physiology and Biological Physics
| E-mail Address: |
mas3x@virginia.edu |
|---|---|
| Telephone: | 434-924-1901 |
| Address: | Medicine/ Endocrinology University of Virginia Box 578 Multistory 7141 Charlottesville, VA 22908 |
Our laboratories major interests are
1) the mechanisms by which neural peptides from the hypothalamus are released in varying pulse patterns and regulate transcription of the pituitary hormones which control metabolism (TSH) and reproduction (LH);
2) mechanisms of estrogen receptor action.
In the first area, we have identified the regions of the pituitary hormone genes which confer hypothalmic regulation, and some of the protein transcription factors which mediate this response. Importantly, we have determined that the LHa and LHb subunit genes, which are regulated physiologically by different pulse frequencies of hypothalamic GnRH, are controlled by different arms of the GnRH intracellular signaling pathways. This appears to be reflected in divergent gene targets for the GnRH signal, and we are working to identify the critical proteins responsible for these timed events in reproduction and development.
In our second area of research, we have found specific isoforms of the estrogen receptor (ER), which mediates the biological effects of the hormone estrogen. We have cloned tissue-specific forms of the ER, including some with unique biological functions. One of these TERP, is found specifically in female pituitary tissue, is highly regulated by estrogen and through the reproductive cycle, and appears to modify or controls the activity of the other ER forms. We are investigating TERP mechanism of action. We are also testing the hypothesis that growth factors act on specific isoforms of ER in human breast cancer, and are part of the process of development of hormone-independent breast cancers.
Selected Publications:
| Bryant WM, Gibson MA, Shupnik MA. | ||
| Stimulation of the novel ER{alpha} intronic TERP-1 promoter by estrogens, androgen, PACAP and forskolin, and autoregulation by TERP-1 protein. Endocrinology. 2005 Oct 6; [Epub ahead of print] PMID: 16210360 [PubMed - as supplied by publisher] |
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| Boerner JL, Gibson MA, Fox EM, Posner ED, Parsons SJ, Silva CM, Shupnik MA. | ||
| Estrogen Negatively Regulates Epidermal Growth Factor (EGF)-Mediated Signal Transducer and Activator of Transcription 5 Signaling in Human EGF Family Receptor-Overexpressing Breast Cancer Cells. Mol Endocrinol. 2005 Nov;19(11):2660-70. Epub 2005 Jun 23. PMID: 15976008 [PubMed - in process] |
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| Bryant W, Snowhite AE, Rice LW, Shupnik MA. | ||
| The estrogen receptor (ER)alpha variant Delta5 exhibits dominant positive activity on ER-regulated promoters in endometrial carcinoma cells. Endocrinology. 2005 Feb;146(2):751-9. Epub 2004 Nov 4. PMID: 15528307 [PubMed - indexed for MEDLINE] |
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| Haisenleder DJ, Burger LL, Aylor KW, Dalkin AC, Walsh HE, Shupnik MA, Marshall JC. | ||
| Testosterone stimulates follicle-stimulating hormone beta transcription via activation of extracellular signal-regulated kinase: evidence in rat pituitary cells. Biol Reprod. 2005 Mar;72(3):523-9. Epub 2004 Oct 27. PMID: 15509729 [PubMed - indexed for MEDLINE] |
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| Shupnik MA. | ||
| Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene. 2004 Oct 18;23(48):7979-89. Review. PMID: 15489915 [PubMed - indexed for MEDLINE] |
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| Abe H, Murao K, Imachi H, Cao WM, Yu X, Yoshida K, Wong NC, Shupnik MA, Haefliger JA, Waeber G, Ishida T. | ||
| Thyrotropin-releasing hormone-stimulated thyrotropin expression involves islet-brain-1/c-Jun N-terminal kinase interacting protein-1. Endocrinology. 2004 Dec;145(12):5623-8. Epub 2004 Sep 2. PMID: 15345675 [PubMed - indexed for MEDLINE] |
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| Murao K, Imachi H, Cao WM, Yu X, Tokumitsu H, Inuzuka H, Wong NC, Shupnik MA, Kobayashi R, Ishida T. | ||
| Role of calcium-calmodulin-dependent protein kinase cascade in thyrotropin (TSH)-releasing hormone induction of TSH and prolactin gene expression. Endocrinology. 2004 Nov;145(11):4846-52. Epub 2004 Aug 12. PMID: 15308608 [PubMed - indexed for MEDLINE] |
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| Tsai HW, Katzenellenbogen JA, Katzenellenbogen BS, Shupnik MA. | ||
| Protein kinase A activation of estrogen receptor alpha transcription does not require proteasome activity and protects the receptor from ligand-mediated degradation. Endocrinology. 2004 Jun;145(6):2730-8. Epub 2004 Mar 19. PMID: 15033909 [PubMed - indexed for MEDLINE] |
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| Curtin D, Ferris HA, Hakli M, Gibson M, Janne OA, Palvimo JJ, Shupnik MA. | ||
| Small nuclear RING finger protein stimulates the rat luteinizing hormone-beta promoter by interacting with Sp1 and steroidogenic factor-1 and protects from androgen suppression. Mol Endocrinol. 2004 May;18(5):1263-76. Epub 2004 Feb 26. PMID: 14988433 [PubMed - indexed for MEDLINE] |
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| Lin VY, Resnick EM, Shupnik MA. | ||
| Truncated estrogen receptor product-1 stimulates estrogen receptor alpha transcriptional activity by titration of repressor proteins. J Biol Chem. 2003 Oct 3;278(40):38125-31. Epub 2003 Jul 23. PMID: 12878603 [PubMed - indexed for MEDLINE] |
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| Haisenleder DJ, Ferris HA, Shupnik MA. | ||
| The calcium component of gonadotropin-releasing hormone-stimulated luteinizing hormone subunit gene transcription is mediated by calcium/calmodulin-dependent protein kinase type II. Endocrinology. 2003 Jun;144(6):2409-16. PMID: 12746302 [PubMed - indexed for MEDLINE] |
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| Schreihofer DA, Rowe DF, Rissman EF, Scordalakes EM, Gustafsson J JA, Shupnik MA. | ||
| Estrogen receptor-alpha (ERalpha), but not ERbeta, modulates estrogen stimulation of the ERalpha-truncated variant, TERP-1. Endocrinology. 2002 Nov;143(11):4196-202. PMID: 12399412 [PubMed - indexed for MEDLINE] |
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| Rissman EF, Heck AL, Leonard JE, Shupnik MA, Gustafsson JA. | ||
| Disruption of estrogen receptor beta gene impairs spatial learning in female mice. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3996-4001. Epub 2002 Mar 12. PMID: 11891272 [PubMed - indexed for MEDLINE] |
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| Shupnik MA. | ||
| Oestrogen receptors, receptor variants and oestrogen actions in the hypothalamic-pituitary axis. J Neuroendocrinol. 2002 Feb;14(2):85-94. Review. PMID: 11849367 [PubMed - indexed for MEDLINE] |
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| Shupnik MA. | ||
| Thyroid hormone suppression of pituitary hormone gene expression. Rev Endocr Metab Disord. 2000 Jan;1(1-2):35-42. Review. PMID: 11704990 [PubMed - indexed for MEDLINE] |
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| Jazaeri AA, Nunes KJ, Dalton MS, Xu M, Shupnik MA, Rice LW. | ||
| Well-differentiated endometrial adenocarcinomas and poorly differentiated mixed mullerian tumors have altered ER and PR isoform expression. Oncogene. 2001 Oct 18;20(47):6965-9. PMID: 11687977 [PubMed - indexed for MEDLINE] |
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| Curtin D, Jenkins S, Farmer N, Anderson AC, Haisenleder DJ, Rissman E, Wilson EM, Shupnik MA. | ||
| Androgen suppression of GnRH-stimulated rat LHbeta gene transcription occurs through Sp1 sites in the distal GnRH-responsive promoter region. Mol Endocrinol. 2001 Nov;15(11):1906-17. PMID: 11682622 [PubMed - indexed for MEDLINE] |
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| Schreihofer DA, Resnick EM, Lin VY, Shupnik MA. | ||
| Ligand-independent activation of pituitary ER: dependence on PKA-stimulated pathways. Endocrinology. 2001 Aug;142(8):3361-8. PMID: 11459779 [PubMed - indexed for MEDLINE] |
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| Schreihofer DA, Stoler MH, Shupnik MA. | ||
| Differential expression and regulation of estrogen receptors (ERs) in rat pituitary and cell lines: estrogen decreases ERalpha protein and estrogen responsiveness. Endocrinology. 2000 Jun;141(6):2174-84. PMID: 10830306 [PubMed - indexed for MEDLINE] |
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| Weck J, Anderson AC, Jenkins S, Fallest PC, Shupnik MA. | ||
| Divergent and composite gonadotropin-releasing hormone-responsive elements in the rat luteinizing hormone subunit genes. Mol Endocrinol. 2000 Apr;14(4):472-85. PMID: 10770486 [PubMed - indexed for MEDLINE] |
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| Resnick EM, Schreihofer DA, Periasamy A, Shupnik MA. | ||
| Truncated estrogen receptor product-1 suppresses estrogen receptor transactivation by dimerization with estrogen receptors alpha and beta. J Biol Chem. 2000 Mar 10;275(10):7158-66. PMID: 10702284 [PubMed - indexed for MEDLINE] |
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| Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW. | ||
| Selective loss of estrogen receptor beta in malignant human colon. Cancer Res. 2000 Jan 15;60(2):245-8. PMID: 10667568 [PubMed - indexed for MEDLINE] |
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| Murphy AZ, Shupnik MA, Hoffman GE. | ||
| Androgen and estrogen (alpha) receptor distribution in the periaqueductal gray of the male Rat. Horm Behav. 1999 Oct;36(2):98-108. PMID: 10506534 [PubMed - indexed for MEDLINE] |
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| Jazaeri O, Shupnik MA, Jazaeri AA, Rice LW. | ||
| Expression of estrogen receptor alpha mRNA and protein variants in human endometrial carcinoma. Gynecol Oncol. 1999 Jul;74(1):38-47. PMID: 10385549 [PubMed - indexed for MEDLINE] |
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| Schreihofer DA, Resnick EM, Soh AY, Shupnik MA. | ||
| Transcriptional regulation by a naturally occurring truncated rat estrogen receptor (ER), truncated ER product-1 (TERP-1). Mol Endocrinol. 1999 Feb;13(2):320-9. PMID: 9973261 [PubMed - indexed for MEDLINE] |
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| Shupnik MA, Pitt LK, Soh AY, Anderson A, Lopes MB, Laws ER Jr. | ||
| Selective expression of estrogen receptor alpha and beta isoforms in human pituitary tumors. J Clin Endocrinol Metab. 1998 Nov;83(11):3965-72. PMID: 9814476 [PubMed - indexed for MEDLINE] |
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| Moffatt CA, Rissman EF, Shupnik MA, Blaustein JD. | ||
| Induction of progestin receptors by estradiol in the forebrain of estrogen receptor-alpha gene-disrupted mice. J Neurosci. 1998 Nov 15;18(22):9556-63. PMID: 9801392 [PubMed - indexed for MEDLINE] |
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| Jeng MH, Shupnik MA, Bender TP, Westin EH, Bandyopadhyay D, Kumar R, Masamura S, Santen RJ. | ||
| Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells. Endocrinology. 1998 Oct;139(10):4164-74. PMID: 9751496 [PubMed - indexed for MEDLINE] |
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| Weck J, Fallest PC, Pitt LK, Shupnik MA. | ||
| Differential gonadotropin-releasing hormone stimulation of rat luteinizing hormone subunit gene transcription by calcium influx and mitogen-activated protein kinase-signaling pathways. Mol Endocrinol. 1998 Mar;12(3):451-7. PMID: 9514161 [PubMed - indexed for MEDLINE] |
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| Friend KE, Resnick EM, Ang LW, Shupnik MA. | ||
| Specific modulation of estrogen receptor mRNA isoforms in rat pituitary throughout the estrous cycle and in response to steroid hormones. Mol Cell Endocrinol. 1997 Aug 8;131(2):147-55. PMID: 9296373 [PubMed - indexed for MEDLINE] |
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| Shupnik MA, Schreihofer DA. | ||
| Molecular aspects of steroid hormone action in the male reproductive axis. J Androl. 1997 Jul-Aug;18(4):341-4. Review. PMID: 9283944 [PubMed - indexed for MEDLINE] |
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| Rice LW, Jazaeri AA, Shupnik MA. | ||
| Estrogen receptor mRNA splice variants in pre- and postmenopausal human endometrium and endometrial carcinoma. Gynecol Oncol. 1997 Apr;65(1):149-57. PMID: 9103405 [PubMed - indexed for MEDLINE] |
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| Shupnik MA. | ||
| Gonadotropin gene modulation by steroids and gonadotropin-releasing hormone. Biol Reprod. 1996 Feb;54(2):279-86. Review. PMID: 8788177 [PubMed - indexed for MEDLINE] |
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| Shupnik MA, Weck J, Hinkle PM. | ||
| Thyrotropin (TSH)-releasing hormone stimulates TSH beta promoter activity by two distinct mechanisms involving calcium influx through L type Ca2+ channels and protein kinase C. Mol Endocrinol. 1996 Jan;10(1):90-9. PMID: 8838148 [PubMed - indexed for MEDLINE] |
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| Friend KE, Ang LW, Shupnik MA. | ||
| Estrogen regulates the expression of several different estrogen receptor mRNA isoforms in rat pituitary. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4367-71. PMID: 7753813 [PubMed - indexed for MEDLINE] |
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| Lahav M, Garmey JC, Shupnik MA, Veldhuis JD. | ||
| Dual actions of phorbol ester on cytochrome P450 cholesterol side-chain cleavage messenger ribonucleic acid accumulation in porcine granulosa cells. Biol Reprod. 1995 May;52(5):972-81. PMID: 7626723 [PubMed - indexed for MEDLINE] |
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