Professor

Email Dr. Carolyn M. Klinge
Phone Number: 502-852-3668
Lab:(502)-852-3668
Fax: (502)-852-3659

Address: 580 S. Preston St., Delia Baxter (Baxter II) Building, Room 221E
Louisville, KY 40202

B.A., 1979, Keuka College
M.S., 1981, The Pennsylvania University, The Milton S. Hershey College of Medicine
PhD, 1984, The Pennsylvania University, The Milton S. Hershey College of Medicine

Research Interests:

Laboratory Personnel:

Al-Rayyan, Numan
Emberts, Celia
Ivanova, Margarita
Litchfield, Lacey
Manavalan, Tissa
Radde, Brandie
Teng, Yun

Dr. Klinge’s research focuses on the molecular mechanisms by which estrogens regulate physiological functions in different cell types including breast and endometrial cancer, lung adenocarcinoma, and the vascular endothelium. The primary focus of the lab is to determine how estrogens regulate the expression of specific genes and microRNAs in a cell-type and promoter context-specific manner. Estrogens bind two different estrogen receptor proteins (ER) in the cell nucleus: ER? and ER?. In her main NIH-funded project, Dr. Klinge and members of her lab group are addressing how estrogens regulate nuclear-mitochondrial signaling by genomic and non-genomic mechanisms and the role of miRNAs in mediating estrogenic signaling in breast cancer cells. The goal of a second NIH-funded project is to determine the role of aberrant microRNA expression in endocrine- resistant breast cancer. Another project is addressing the role of COUP-TFII in antiestrogen-sensitivity and the mechanism for the decrease in COUP-TFII expression in endocrine-resistant breast cancer. A fourth project is supported by a grant from Joan’s Legacy and the Lungevity Foundations. In that work, Dr. Klinge and her group are examining the mechanisms accounting the gender disparity in lung adenocarcinoma and the role of coregulators and ER?-interacting proteins in this process. In a fifth project, supported by the American Heart Association, Dr. Klinge is examining how estradiol and the dietary chemical resveratrol, which is enriched in red wine, mediate cardioprotective effects in vascular endothelium. This project is examining intracellular mechanisms of estrogen action that are independent of nuclear ER activity. Two collaborative research projects are aimed at determining the anti-cancer activity of anacardic acid and the role of estrogen receptor signaling in thyroid cancer.

Selected Publications:

Mattingly KA, Klinge CM. Diesel exhaust particulate extracts inhibit transcription of nuclear respiratory factor-1 and cell viability in human umbilical vein endothelial cells. Arch Toxicol. 2011 Nov 22. [Epub ahead of print] PMID:22105178

Manavalan TT, Teng Y, Appana SN, Datta S, Kalbfleisch TS, Li Y, Klinge CM. Differential expression of microRNA expression in tamoxifen-sensitive MCF-7 versus tamoxifen-resistant LY2 human breast cancer cells. Cancer Lett. 2011 Dec 26;313(1):26-43. Epub 2011 Sep 10. PMID: 21955614

Ivanova M, Abner S, Pierce W Jr, Klinge C. Ligand-dependent differences in estrogen receptor beta-interacting proteins identified in lung adenocarcinoma cells corresponds to estrogenic responses. Proteome Sci. 2011 Sep 27;9(1):60. PMID: 21951318

Klinge CM, Radde BN, Imbert-Fernandez Y, Teng Y, Ivanova MM, Abner SM, Martin AL. Targeting the Intracellular MUC1 C-terminal Domain Inhibits Proliferation and Estrogen Receptor Transcriptional Activity in Lung Adenocarcinoma Cells. Mol Cancer Ther. 2011 Nov;10(11):2062-71. Epub 2011 Aug 23. PMID: 21862684

Imbert-Fernandez Y, Radde BN, Teng Y, Young WW Jr, Hu C, Klinge CM. MUC1/A and MUC1/B splice variants differentially regulate inflammatory cytokine expression. Exp Eye Res. 2011 Nov;93(5):649-57. Epub 2011 Aug 16. PMID: 21854773

Porter AM, Klinge CM, Gobin AS. Covalently grafted VEGF165 in hydrogel models upregulates the cellular pathways associated with angiogenesis. Am J Physiol Cell Physiol. 2011 Nov;301(5):C1086-92. Epub 2011 Jul 27. PMID: 21795519

Ivanova MM, Luken KH, Zimmer AS, Lenzo FL, Smith RJ, Arteel MW, Kollenberg TJ, Mattingly KA, Klinge CM. Tamoxifen increases nuclear respiratory factor 1 transcription by activating estrogen receptor beta and AP-1 recruitment to adjacent promoter binding sites. FASEB J. 2011 Apr;25(4):1402-16. Epub 2011 Jan 13. PMID: 21233487

Porter AM, Klinge CM, Gobin AS. Biomimetic hydrogels with VEGF induce angiogenic processes in both hUVEC and hMEC. Biomacromolecules. 2011 Jan 10;12(1):242-6. Epub 2010 Dec 3. PMID: 21128597

Schultz, D.J., Wickramasinghe, N.S., Ivanova, M.M., Isaacs, S.M., Riggs, K.A., Dougherty, S.M., Imbert, Y., Chen, C., Mattingly, K.A., and Klinge, C.M. Anacardic acid inhibits breast cancer cell proliferation by inhibition of estrogen receptor- estrogen response element binding and gene transcription. Mol Cancer Ther. 9:594-605, 2010. Epub 2010 Mar 2. PMID: 20197399

Ivanova, M.M., Mazhawidza, W., Dougherty, S.M., and Klinge, C.M. Sex differences in estrogen receptor subcellular location and activity in lung adenocarcinoma cells. American Journal of Respiratory Cell and Molecular Biology 42: 320-330, 2010. Epub 2009 Jun 25. PMID: 19556604 PMCID: PMC2830404

Kumar, A. *, Klinge, C.M. *, and Goldstein, R.E. Estradiol-induced proliferation of papillary and follicular thyroid cancer cells is mediated by estrogen receptors alpha and beta. Int. J. Oncol. 36: 1067-1080, 2010. *AK and CMK are equal first authors. CMK is the corresponding author. PMID: 20372779

Klinge, C.M., Riggs, K.A., Wickramasinghe, N.S., McConda, D.B., and Barry, P.N. Estrogen receptor alpha 46 is reduced in tamoxifen resistant breast cancer cells and re-expression inhibits cell proliferation and estrogen receptor alpha 66-regulated target gene transcription. Mol. Cell. Endocrinol. 323: 268-276, 2010.

Wickramasinghe, N.S., Manavalan, T.T., Dougherty, S.M., Riggs, K.A., Li, Y., and Klinge, C.M. Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids Res. 37: 2584-2595, 2009.

Ivanova, M.M., Mazhawidza, W., Dougherty, S.M., Minna, J.D. and Klinge, C.M. Activity and intracellular location of estrogen receptors alpha and beta in human bronchial epithelial cells (HBECs). Mol. Cell. Endocrinol. 305:12-21, 2009.

Sanada, N., Gotoh, Y., Shimazaw, R., Klinge, C.M., and Kizu, R. Repression of activated aryl hydrocarbon receptor-induced transcriptional activation by 5?-dihydrotestosterone in human prostate cancer LNCaP and human breast cancer T47D cells. J. Pharmacol. Sci.109: 380-387, 2009.

Klinge, C.M. Estrogen regulation of microRNA expression. Current Genomics 10: 169-183, 2009.

Klinge, C.M. Estrogenic Control of Mitochondrial Function and Biogenesis. J. Cell. Biochem. 105:1342-1351, 2008.

Lu, Z., Liu, M., Stibinskis, V. Klinge, C.M., Ramos, K.S., Colburn, N.H., and Li, Y. MicroRNA-21 Promotes Cell Transformation by Targeting the Programmed Cell Death 4 Gene. Oncogene 27: 4373-9, 2008.

Klinge, C.M., Wickramasinghe, N.S., Ivanova, M.M., and Dougherty, S.M. Resveratrol stimulates nitric oxide production by increasing estrogen receptor alpha-Src-Caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells. FASEB J. 22: 2185-2197, 2008.

Mattingly, K.A., Ivanova, M.M., Riggs, K.A., Wickramasinghe, N.S., Barch, M.J., and Klinge, C.M. Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis Mol. Endocrinol. 22:609-622, 2008.

Sumanasekera, W.K., Ivanova, M.M., Johnston, B.J., Dougherty, S.M., Sumanasekera, G.U., Myers, S.R., Ali, Y., Kizu, R. and Klinge, C.M. Rapid effects of diesel exhaust particulate extracts on intracellular signaling in human endothelial cells. Toxicological Letters 174: 61-73, 2007.

Sumanasekera, W.K., Sumanasekera, G.S., Keynton, R.S., and Klinge, C.M., Estradiol and dihydrotestosterone regulate endothelial cell barrier function following hypergravity-induced alterations in MAPK activity. Am. J. Physiol. Cell Physiol. 293: C566-573, 2007.

Vijayanathan, V., Greenfield, N.J., Thomas, T.J., Gallo, M.A., Ivanova, M.M., Tyulmenkov, V., Klinge, C.M., and Thomas, T. Differential Effects of Estradiol and 4-Hydroxytamoxifen on DNA Recognition and Stabilization of Estrogen Receptor Beta. Biochem. Cell Biol. 85:1-10, 2007.

Ivanova, M.M., Mattingly, K.A., and Klinge, C.M. Baculovirus Lytic Infection Yields Higher Estrogen Receptor beta than Stably-transformed Sf21 Cells. Applied Microbiology and Biotechnology 74:1256-63, 2007.

Sumanasekera, W.K., Zhao, L., Ivanova, M., Morgan, D.D., Noisin, E.L., Keynton, R.S., and Klinge, C.M. Effect of estradiol and dihydrotestosterone on hypergravity-induced MAPK signaling and occludin expression in human umbilical vein endothelial cells. Cell Tis. Res. 324: 243-53, 2006.

Dougherty, S.M., Mazhawidza, W., Bohn, A.S., Robinson, K.A., Mattingly, K.A., Blankenship, K.A., Huff, M.O., McGregor, W.G., and Klinge, C.M. Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells. Endocrine-Rel. Cancer 13: 113-134, 2006.

Schultz, D.J., Wickramasinghe, N.S., and Klinge, C.M. Biosynthesis and bioactivity of anacardic acid. Recent Advances in Phytochemistry, Romeo, J. (Ed.), volume 40: 131-156, 2006.

Klinge, C.M., Blankenship, K.A., Risinger, K.E., Bhatnagar, S., Noisin, E.L., Sumanasekera, W.K., Zhao, L. Brey, D.M., and Keynton, R.S. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J. Biol. Chem. 280: 7460-7468, 2005.

Klinge, C.M., Jernigan, S.C., Mattingly, K.A., Risinger, K.E., and Zhang, J. Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors. J. Mol. Endocrinol. 33: 387-410, 2004.

Ramsey, T.L., Jernigan, S.C., Risinger, K.E., Mattingly, K.A., and Klinge, C.M. Estrogen receptor beta isoforms exhibit differences in ligand-activated transcriptional activity in an estrogen response element sequence-dependent manner. Endocrinology 145: 149-160, 2004.

Okamura, K., Kizu, R., Toriba, A., Murahashi, T., Mizokami, A., Burnstein, K.L., Klinge, C.M., Hayakawa, K. Antiandrogenic activity of extracts of diesel exhaust particles emitted from the diesel engine truck under different engine loads and speeds. Toxicology 195: 243-254 2004.

Kulakosky, P.C. and Klinge, C.M. Maximizing production of estrogen receptor b with the baculovirus expression system. BioTechniques 34: 334-343, 2003.

Ramsey, T.L., Jernigan, S.C., Risinger, K.E., Mattingly, K.A., and Klinge, C.M. Estrogen receptor beta isoforms exhibit differences in ligand-activated transcriptional activity in an estrogen response element sequence-dependent manner. Endocrinology, in press, 2003.

Klinge, C.M., Jernigan, S.C., Risinger, K.E., and Lee, J.E. The agonist activity of tamoxifen is inhibited by the SHP orphan nuclear receptor in human endometrial cancer cells. Endocrinology 143, 853-867, 2002.

Kulakosky, P.C., McCarty, M.A., Jernigan, S.C., Risinger, K.E., and Klinge, C.M. Response element sequence modulates estrogen receptor a and b affinity and activity J. Mol. Endocrinol. 29:137-152, 2002.

Klinge, C.M. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res.29: 2905-2919, 2001. (Supplementary material available online: http://nar.oupjournals.org/cgi/content/full/29/14/2905/DC1).