Margaret A. Shupnik

Margaret A. Shupnik

Margaret A. Shupnik, Ph.D.

Endocrinology, and
Molecular Physiology and Biological Physics


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:

Introduction to the year in basic science series...2009.Shupnik MA. Mol Endocrinol. 2010 Jan;24(1):250-1. Epub 2009 Dec 17.PMID: 20019125

Differential regulation of gonadotropin-releasing hormone neuron activity and membrane properties by acutely applied estradiol: dependence on dose and estrogen receptor subtype.Chu Z, Andrade J, Shupnik MA, Moenter SM. J Neurosci. 2009 Apr 29;29(17):5616-27.PMID: 19403828

Proteasome regulation of dynamic transcription factor occupancy on the GnRH-stimulated luteinizing hormone beta-subunit promoter. Walsh HE, Shupnik MA. Mol Endocrinol. 2009 Feb;23(2):237-50. Epub 2008 Dec 18.PMID: 19095772

Decreased BRCA1 confers tamoxifen resistance in breast cancer cells by altering estrogen receptor-coregulator interactions. Wen J, Li R, Lu Y, Shupnik MA. Oncogene. 2009 Jan 29;28(4):575-86. Epub 2008 Nov 10.PMID: 18997820

Novel actions of estrogen to promote proliferation: integration of cytoplasmic and nuclear pathways. Fox EM, Andrade J, Shupnik MA. Steroids. 2009 Jul;74(7):622-7. Epub 2008 Nov 5. Review.PMID: 18996136

Introduction to The Year in Basic Science series. Shupnik MA. Mol Endocrinol. 2008 Dec;22(12):2741-2. Epub 2008 Oct 9.PMID: 18845669

Signal transducer and activator of transcription 5b, c-Src, and epidermal growth factor receptor signaling play integral roles in estrogen-stimulated proliferation of estrogen receptor-positive breast cancer cells. Fox EM, Bernaciak TM, Wen J, Weaver AM, Shupnik MA, Silva CM. Mol Endocrinol. 2008 Aug;22(8):1781-96. Epub 2008 Jun 11.PMID: 18550772

ERbeta in breast cancer--onlooker, passive player, or active protector? Fox EM, Davis RJ, Shupnik MA. Steroids. 2008 Oct;73(11):1039-51. Epub 2008 Apr 20. Review.PMID: 18501937

Pulsatile gonadotropin-releasing hormone stimulation of gonadotropin subunit transcription in rat pituitaries: evidence for the involvement of Jun N-terminal kinase but not p38.Haisenleder DJ, Burger LL, Walsh HE, Stevens J, Aylor KW, Shupnik MA, Marshall JC.Endocrinology. 2008 Jan;149(1):139-45. Epub 2007 Oct 11.PMID: 17932215

Estrogen enhances gonadotropin-releasing hormone-stimulated transcription of the luteinizing hormone subunit promoters via altered expression of stimulatory and suppressive transcription factors. Kowase T, Walsh HE, Darling DS, Shupnik MA. Endocrinology. 2007 Dec;148(12):6083-91. Epub 2007 Sep 6.PMID: 17823254

Luteinizing hormone beta promoter stimulation by adenylyl cyclase and cooperation with gonadotropin-releasing hormone 1 in transgenic mice and LBetaT2 Cells. Ferris HA, Walsh HE, Stevens J, Fallest PC, Shupnik MA. Biol Reprod. 2007 Dec;77(6):1073-80. Epub 2007 Aug 15.PMID: 17699734

Estrogen receptor-beta: why may it influence clinical outcome in estrogen receptor-alpha positive breast cancer? Shupnik MA. Breast Cancer Res. 2007;9(3):107.PMID: 17617929

Integration of steroid and growth factor pathways in breast cancer: focus on signal transducers and activators of transcription and their potential role in resistance. Silva CM, Shupnik MA. Mol Endocrinol. 2007 Jul;21(7):1499-512. Epub 2007 Apr 24. Review.PMID: 17456797

Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Riggins RB, Thomas KS, Ta HQ, Wen J, Davis RJ, Schuh NR, Donelan SS, Owen KA, Gibson MA, Shupnik MA, Silva CM, Parsons SJ, Clarke R, Bouton AH.Cancer Res. 2006 Jul 15;66(14):7007-15.PMID:

Mechanisms for pulsatile regulation of the gonadotropin subunit genes by GNRH1. Ferris HA, Shupnik MA. Biol Reprod. 2006 Jun;74(6):993-8. Epub 2006 Feb 15. Review.PMID:

Stimulation of the novel estrogen receptor-alpha intronic TERP-1 promoter by estrogens, androgen, pituitary adenylate cyclase-activating peptide, and forskolin, and autoregulation by TERP-1 protein.Bryant WM, Gibson MA, Shupnik MA. Endocrinology. 2006 Jan;147(1):543-51. Epub 2005 Oct 6.PMID:

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.Boerner JL, Gibson MA, Fox EM, Posner ED, Parsons SJ, Silva CM, Shupnik MA. Mol Endocrinol. 2005 Nov;19(11):2660-70. Epub 2005 Jun 23.PMID: 15976008

The estrogen receptor (ER)alpha variant Delta5 exhibits dominant positive activity on ER-regulated promoters in endometrial carcinoma cells. Bryant W, Snowhite AE, Rice LW, Shupnik MA.Endocrinology. 2005 Feb;146(2):751-9. Epub 2004 Nov 4.PMID:

Testosterone stimulates follicle-stimulating hormone beta transcription via activation of extracellular signal-regulated kinase: evidence in rat pituitary cells. Haisenleder DJ, Burger LL, Aylor KW, Dalkin AC, Walsh HE, Shupnik MA, Marshall JC. Biol Reprod. 2005 Mar;72(3):523-9. Epub 2004 Oct 27.PMID:

Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Shupnik MA. Oncogene. 2004 Oct 18;23(48):7979-89. Review.PMID: 15489915

Thyrotropin-releasing hormone-stimulated thyrotropin expression involves islet-brain-1/c-Jun N-terminal kinase interacting protein-1. Abe H, Murao K, Imachi H, Cao WM, Yu X, Yoshida K, Wong NC, Shupnik MA, Haefliger JA, Waeber G, Ishida T. Endocrinology. 2004 Dec;145(12):5623-8. Epub 2004 Sep 2.PMID: 15345675

Role of calcium-calmodulin-dependent protein kinase cascade in thyrotropin (TSH)-releasing hormone induction of TSH and prolactin gene expression. Murao K, Imachi H, Cao WM, Yu X, Tokumitsu H, Inuzuka H, Wong NC, Shupnik MA, Kobayashi R, Ishida T. Endocrinology. 2004 Nov;145(11):4846-52. Epub 2004 Aug 12.PMID: 15308608

Protein kinase A activation of estrogen receptor alpha transcription does not require proteasome activity and protects the receptor from ligand-mediated degradation. Tsai HW, Katzenellenbogen JA, Katzenellenbogen BS, Shupnik MA. Endocrinology. 2004 Jun;145(6):2730-8. Epub 2004 Mar 19.PMID: 15033909

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. Curtin D, Ferris HA, Hkli M, Gibson M, Jnne OA, Palvimo JJ, Shupnik MA. Mol Endocrinol. 2004 May;18(5):1263-76. Epub 2004 Feb 26.PMID: 14988433

Truncated estrogen receptor product-1 stimulates estrogen receptor alpha transcriptional activity by titration of repressor proteins. Lin VY, Resnick EM, Shupnik MA. J Biol Chem. 2003 Oct 3;278(40):38125-31. Epub 2003 Jul 23.PMID: 12878603

The calcium component of gonadotropin-releasing hormone-stimulated luteinizing hormone subunit gene transcription is mediated by calcium/calmodulin-dependent protein kinase type II. Haisenleder DJ, Ferris HA, Shupnik MA. Endocrinology. 2003 Jun;144(6):2409-16.PMID:

Estrogen receptor-alpha (ERalpha), but not ERbeta, modulates estrogen stimulation of the ERalpha-truncated variant, TERP-1. Schreihofer DA, Rowe DF, Rissman EF, Scordalakes EM, Gustafsson J J, Shupnik MA. Endocrinology. 2002 Nov;143(11):4196-202.PMID: 12399412

Disruption of estrogen receptor beta gene impairs spatial learning in female mice. Rissman EF, Heck AL, Leonard JE, Shupnik MA, Gustafsson JA. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3996-400. Epub 2002 Mar 12.PMID: 11891272

Oestrogen receptors, receptor variants and oestrogen actions in the hypothalamic-pituitary axis.Shupnik MA. J Neuroendocrinol. 2002 Feb;14(2):85-94. Review.PMID: 11849367

Thyroid hormone suppression of pituitary hormone gene expression. Shupnik MA. Rev Endocr Metab Disord. 2000 Jan;1(1-2):35-42. Review.PMID: 11704990

Well-differentiated endometrial adenocarcinomas and poorly differentiated mixed mullerian tumors have altered ER and PR isoform expression. Jazaeri AA, Nunes KJ, Dalton MS, Xu M, Shupnik MA, Rice LW. Oncogene. 2001 Oct 18;20(47):6965-9.PMID: 11687977

Androgen suppression of GnRH-stimulated rat LHbeta gene transcription occurs through Sp1 sites in the distal GnRH-responsive promoter region. Curtin D, Jenkins S, Farmer N, Anderson AC, Haisenleder DJ, Rissman E, Wilson EM, Shupnik MA. Mol Endocrinol. 2001 Nov;15(11):1906-17.PMID: 11682622

Ligand-independent activation of pituitary ER: dependence on PKA-stimulated pathways. Schreihofer DA, Resnick EM, Lin VY, Shupnik MA. Endocrinology. 2001 Aug;142(8):3361-8.PMID: 11459779

Differential expression and regulation of estrogen receptors (ERs) in rat pituitary and cell lines: estrogen decreases ERalpha protein and estrogen responsiveness. Schreihofer DA, Stoler MH, Shupnik MA. Endocrinology. 2000 Jun;141(6):2174-84.PMID:

Divergent and composite gonadotropin-releasing hormone-responsive elements in the rat luteinizing hormone subunit genes. Weck J, Anderson AC, Jenkins S, Fallest PC, Shupnik MA. Mol Endocrinol. 2000 Apr;14(4):472-85.PMID:

Truncated estrogen receptor product-1 suppresses estrogen receptor transactivation by dimerization with estrogen receptors alpha and beta. Resnick EM, Schreihofer DA, Periasamy A, Shupnik MA. J Biol Chem. 2000 Mar 10;275(10):7158-66.PMID: 10702284

Selective loss of estrogen receptor beta in malignant human colon. Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW. Cancer Res. 2000 Jan 15;60(2):245-8.PMID: 10667568

Androgen and estrogen (alpha) receptor distribution in the periaqueductal gray of the male Rat. Murphy AZ, Shupnik MA, Hoffman GE. Horm Behav. 1999 Oct;36(2):98-108.PMID: 10506534

Expression of estrogen receptor alpha mRNA and protein variants in human endometrial carcinoma. Jazaeri O, Shupnik MA, Jazaeri AA, Rice LW. Gynecol Oncol. 1999 Jul;74(1):38-47.PMID: 10385549

Transcriptional regulation by a naturally occurring truncated rat estrogen receptor (ER), truncated ER product-1 (TERP-1). Schreihofer DA, Resnick EM, Soh AY, Shupnik MA.Mol Endocrinol. 1999 Feb;13(2):320-9.PMID: 9973261