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Charles V Clevenger, MD,PhD
Professor of Pathology
Lurie 4-107
303 E. Superior Street
Chicago, IL 60611
clevenger@northwestern.edu
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Phone: (312) 503-5750
Fax: (312) 503-8240
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Anatomic Pathology Division
Cytopathology
Medical School
Northwestern University (MD - `87; PhD, Tumor Cell Biology - `86)
Site of Residency
University of Pennsylvania
Research Interests
The research focus in Dr. Clevenger's lab is the characterization of prolactin (PRL) receptor signal transduction and function as it pertains to breast cancer and mammary gland development. The PRL receptor (PRLr) is a member of the growth factor/cytokine receptor family, which includes the receptors for interleukin 2-7, GM-CSF, erythropoietin, and growth hormone. Within humans, PRL functions at the endocrine and autocrine/paracrine levels as a growth and differentiation factor within the breast, a hypothesis first postulated by our laboratory. Indeed, recent data we have also demonstrated that PRL serves as a chemoattractant for human breast carcinoma. Therefore, one of our major aims is the characterization of those mechanisms that regulate PRL/PRLr expression and action in both normal and neoplastic tissues. PRL action in human tissues is mediated by six prolactin receptor isoforms, three of which were initially identified and characterized by our lab. The molecular dissection of PRL receptor isoform structure/function, therefore, is another research focus. These studies utilize both biochemical and biophysical approaches to examine PRL-PRLr binding and the interaction of the PRLr with its associated transduction pathways that include JAK/Stat, Vav2/Rac, Fyn, Tec, and Bcl-2/Bag-1. In addition to these non-genomic transduction pathways, we have recently identified a direct genomic action of PRL on gene expression. This action is mediated by the chaperone cyclophilin B (CypB), which retrotransports endocytosed ligand into the nucleus, where the PRL/CypB complex directly interacts with and activates the Stat5 transcription factor. The PRL/CypB complex serves to activate Stat5 by blocking the association of the SUMO E3 ligase PIAS3 and its attendant sumolyation of Stat5; furthermore, the association with the Cyp-regulated proto-oncogene c-myb is stimulated. As such our findings present vantage points in the development of novel therapies aimed at modulating PRL action during the differentiation of the human breast and the pathogenesis of malignancy in this tissue.
Selected Publications
Gadd SL and Clevenger CV: Ligand-independent pre-dimerization of the
human prolactin receptor isoforms: Functional implications. Molecular
Endocrinology, 20:2734-2746, 2006.
Miller SL Antico G, Raghunath PN, Tomaszewski JE, Clevenger CV. Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells. Oncogene, 26:4668-4678, 2007.
McHale K, Tomaszewski JE Puthiyaveettil R, LiVolsi VA, Clevenger CV. Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma. Mod Pathol, 21:565-571, 2008.
Clevenger CV, Zheng J, Jablonski L, Galbaugh T, Feng F. From bench to bedside: Future potential for translation of prolactin inhibitors for the treatment of human breast cancer. J Mammary Gland Biol Neoplasia,13:147-156, 2008.
Zheng J, JE Koblinski J, Dutson LV, Feeney YB, Clevenger CV. Prolyl isomerase cyclophilin A regulation of Janus-activated kinase 2 and the progression of human breast cancer. Cancer Res, 68:7769-7778, 2008.
Fang F, Flegler AJ, Whitehead JL, Du P, Lin S, Clevenger CV. Expression of cyclophilin B is associated with malignant progression and
regulation of genes implicated in the pathogenesis of breast cancer. Am J Pathol, 174:297-308, 2009.
Fang F, Rycyzyn MA, Clevenger CV. Role of c-Myb during PRL-induced Stat5 signaling in breast cancer cells. Endocrinology, 150:1597-1606, 2009.
Bauer K, Kretzchmer A, Cvijic H, Blumert C, Loffler D,
Brocke-Heidrich K, Schiene-Fischer C, Fischer G, Sinz A, Clevenger CV, Horn F. Cyclophilins contribute to Stat3 signaling and survival of multiple
myeloma cells. Oncogene, In press, 2009.
View more Publications by Charles V Clevenger, MD,PhD
listed in the National Library of Medicine (PubMed)
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