Welcome to Nephew Laboratory
Kenneth Patrick Nephew, Ph.D.
Research assistant professor
Research associate, Indiana University, 2011-2013
Postdoctoral Research Fellow, Indiana University, 2007-2011
Ph.D., Chinese Academy of Medical Sciences & Peking Union Medical College, China, 2006
M.D., Peking University, Medicine, China, 2001
B.S.: Genetics and Molecular Pharmacology; Purdue Univ, 2013
Ph.D., Indiana University, 2013-present
M.S., Indiana University, 2013
B.A., University of California, Santa Barbara, 2011
Xingyue (Agnes) Zong
B.S., China Medical University, China, 2010-2015
Postdoctoral Research Fellow
Visiting Scholar, Harper Cancer Research Institute, University of Notre Dame, Aug’2017 - pres.
Postdoctoral Research Associate, Harper Cancer Research Institute, University of Notre Dame, Jan-Jul’2017
Ph.D., Department of Biological Sciences, University of Notre Dame, 2011-2017
M.S., Dept of Pathology and Anatomical Sciences, University of Missouri – Columbia, 2009-2011
Residency, Internal Medicine, Kharkiv National Medical University, Ukraine, 2006-2008
M.S., Internal Medicine, Kharkiv National Medical University, Ukraine, 2006-2008
M.D., Kharkiv State Medical University (KSMU), Ukraine, 2000-2006
B.S., Southern Medical University, China, 2009-2014
Hypothetical model of depicting the role of NEDD8 (neural precursor cell-expressed developmentally down-regulated) pathway in proteasome-mediated degradation of estrogen receptor alpha (ERα). The physical interaction between Uba3 and ERα promotes the functional recruitment and activation of a cullin-based ubiquitin-protin ligase to augment receptor polyubiquitination. The antiestrogen ICI 182,780 is known to induce ER degradation. In human MCF7 breast cancer cells modified to contain a disrupted NEDD8 pathway, ICI 182,780 degradation of ERα was impaired, and the antiestrogen was ineffective at inhibiting cell proliferation. This study provides the first evidence linking nuclear receptor degradation with the NEDD8 pathway and the ubiquitin-proteasome system, suggesting that the two pathways can act together to modulate ERα turnover and cellular responses to estrogens. Based on our observation that an intact NEDD8 pathway is essential for the antiproliferation activity of the ICI 182,780 in ERα positive breast cancer cells, we propose that disruptions in the NEDD8 pathway provide a mechanism by which breast cancer cells acquire antiestrogen resistance while retaining expression of ERα.
The NEDD8 Pathway Is Required for Proteasome-Mediated Degradation of Human Estrogen Receptor (ER)-α and Essential for the Antiproliferative Activity of ICI 182,780 in ERα-Positive Breast Cancer Cells
Meiyun Fan Robert M. Bigsby Kenneth P. Nephew
Cytoreductive surgery followed by platinum/taxane results in complete response in 70&percent; of ovarian cancer patients, but most patients will relapse with drug-resistant disease within 18 months. An emerging model for the development of drug-resistant tumors invokes a pool of self-renewing malignant progenitors known as cancer-initiating cells. Zhang and colleagues identify and characterize a subpopulation of ovarian cancer–initiating cells (OCICs) capable of serial propagation of their original tumor phenotype in animals. Stemness properties of OCICs include enhanced chemoresistance to cisplatin or paclitaxel and upregulation of stem cell markers Bmi-1, stem cell factor, Notch-1, Nanog, nestin, ABCG2, and Oct-4. To identify an OCIC cell surface phenotype, immunostaining showed significant up-regulation of the hyaluronate acid receptor CD44 and stem cell factor receptor CD117, a tyrosine kinase oncoprotein. Isolated CD44+CD117+ cells could also serially propagate theiroriginal tumor phenotype in animals. These findings suggest that epithelial ovarian cancers derive from a subpopulation of CD44+CD117+ cells, thus representing a possible therapeutic target for this devastating disease. For details, see the article by Zhang et al. on page 4311 of this issue.