Joseph Locker, MD, PhD
Professor of Pathology


Dr. Locker is a member of the Division of Molecular Anatomic Pathology.

Office Location:
BST South S421
200 Lothrop Street
Pittsburgh, PA 15261
Contact Information:
Office Telephone: 412-648-9701
Lab Telephone: 412-648-9775 and 412-648-9656
Email: lockerj@upmc.edu
     jlocker@pitt.edu

Clinical Expertise

  • Molecular diagnostics
  • Analysis of mutations, translocations, and copy number variation
  • Anatomic pathology
  • Immunohistochemistry

Research Interests

My research integrates basic transcriptional mechanisms of gene expression in the liver. One project focuses on cancer promotion by comparing the various transcriptional pathways that activate hepatocyte cell proliferation. Phenobarbital and other drugs that activate CAR-a nuclear receptor transcription factor-promotes cancer by inducing hyperplasia in the intact liver. In contrast, partial hepatectomy or cell injury induces liver regeneration. The timing of proliferation and the sequence of gene activations differ greatly between hyperplasia and regeneration, and our work indicates that CAR directly targets genes that activate a distinctive cancer-promoting cell cycle. Liver regeneration activates cell proliferation by a more indirect pathway, starting with growth factor signal transduction pathways. Our recent work also showed how CAR interacts with other nuclear receptors to alter transcriptional control of metabolism.

A second project looks at a different aspect of hepatocyte transcriptional regulation and focuses on cirrhosis. Prior studies showed that hepatocytes in end-stage cirrhosis have lost transcriptional programing, primarily by downregulation of HNF4. This nuclear receptor transcription factor is a central regulator of hepatocyte phenotype. Our project therefore studies how chronic injury and inflammation deregulate expression of HNF4 and alter the hepatocyte phenotype.

Both projects use contemporary NextGen sequencing methodologies for genome wide characterization of gene expression, transcription factor binding, and chromatin remodeling associated with gene activation and repression.

Education

  • BS - University of Pittsburgh, 1967
  • PhD - University of Chicago, 1974
  • MD - University of Chicago, 1975

NIH Research

View Dr. Locker's NIH RePORT on nih.gov

Selected Publications

View Dr. Locker's publications on PubMed

  • Harris T, Pan Q, Sironi S, Lutz D, Tian J, Sapkar J, Perez-Soler R, Keller S, Locker J. (2011) Both gene amplification and allelic loss occur at 14q13.3 in lung cancer. Clin Cancer Res 17, 690-9. PMID:21148747
  • Tian J, Huang H, Liebermann D, Ledda-Columbano GM, Columbano A, Locker J. (2011) Gadd45 is an inducible coactivator of transcription that facilitates rapid liver growth. J Clin Invest 121, 4491-4502. PMID: 21965327
  • Friedl P, Locker J, Sahai E, Segall, JE (2012) Classifying collective cancer cell invasion. Nature Cell Biol 14, 777 - 783. PMID:22854810
  • Tian J, Locker J (2013) Gadd45 in the liver: Signal transduction and transcriptional mechanisms, Adv Exp Biol Med 793, 69-80. PMID: 24104474.
  • Yovchev MI, Xue Y, Shafritz DA, Locker J, Oertel M. (2014) Repopulation of the fibrotic/cirrhotic rat liver by transplanted hepatic stem/progenitor cells and mature hepatocytes. Hepatology 2014 59, 284-95. PMID: 23840008.
  • Lin J, Marquardt G, Mullapudi N, Wang T, Han W, Shi M, Keller S, Zhu C, Locker J, Spivack SD (2014) Lung cancer transcriptomes refined with laser capture microdissection. Am J Path, 184, 2868-84. PMID: 25128906.
  • Nishikawa T, Bell A, Brooks JM, Setoyama K, Melis M, Han B, Fukumitsu K, Handa K, Tian J, Kaestner KH, Vodovotz Y, Locker J, Soto-Gutierrez A, Fox IJ. (2015) Resetting the transcription factor network reverses terminal chronic hepatic failure. J Clin Invest, 125, 1533-44. PMID: 25774505
  • Yovchev MI, Locker J, Oertel M (2016) Biliary fibrosis drives liver repopulation and phenotype transition of transplanted hepatocytes. J Hepatol, 64:1348-57. PMID:26855174
  • Zhao H, Lu Z, Bauzon F, Fu H, Cui J, Locker J, and Zhu L (2017) p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer. Oncogene, 36:60-70. PMID: 27181203
  • Haridoss H, Yovchev MI, Schweizer H, Megherhi S, Beecher M, Locker J, Oertel M (2017) Activin A is a prominent autocrine regulator of hepatocyte growth arrest, Hepatol Commun, 1:852?870. PMID: 29404498
  • Tian J, Marino R, Johnson C, Locker J. (2018) Binding of drug-activated CAR/Nr1i3 alters metabolic regulation in the liver. iScience, 9:209-228. PMID: 30396153
  • Yovchev MI, Lee, EJ, Rodriguez-Silva W, Locker J, Oertel M (2019) Biliary obstruction promotes multilineage differentiation of hepatic stem cells, Hepatol Commun, 3(8):1137-1150. PMID: 31388633
  • Bharat B, Banerjee S, Paranjpe S, Koral K, Mars WM, Stoops JW, Orr A, Bowen WC, Locker J, Michalopoulos, GM. (2019) Pharmacologic Inhibition of EGFR Suppresses Non-alcoholic Fatty Liver Disease in Murine Fast-food Diet Model, Hepatology, in press. PMID:31063640