Joseph Locker, MD, PhD
Professor of Pathology
Dr. Locker is a member of the Division of Molecular Anatomic Pathology.
BST South S421
200 Lothrop Street
Pittsburgh, PA 15261
Office Telephone: 412-648-9701
Lab Telephone: 412-648-9775 and 412-648-9656
- Molecular diagnostics
- Analysis of mutations, translocations, and copy number variation
- Anatomic pathology
Research in our laboratory integrates basic transcriptional mechanisms of gene expression with liver disease or cancer promotion. One major project focuses on tumor promotion by comparing the various transcriptional pathways that activate hepatocyte cell proliferation. Phenobarbital and other drugs that activate CAR— a nuclear receptor transcription factor—promote cancer by inducing hyperplasia, i.e., cell proliferation in the intact liver. In contrast, partial hepatectomy or cell injury induces the compensatory cell proliferation of liver regeneration. The timing of proliferation and the sequence of gene activations differ greatly between hyperplasia and regeneration, and our work suggests a model in which CAR’s direct target genes activate the cancer-promoting cell cycle. Cell cycle activation in liver regeneration is more indirect, starting with cytokine and growth factor activated signal transduction pathways.
A new project looks at a different aspect of hepatocyte transcriptional regulation and focuses on cirrhosis. Work by our collaborator, Ira Fox, 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, leading to the stable loss of the mature hepatocyte phenotype.
Both transcriptional projects utilize contemporary NextGen sequencing methodologies for genome wide characterization of gene expression, transcription factor binding, and chromatin remodeling associated with gene activation and repression.
A third project arose from our liver research that discovered of Nkx2-8, a homeodomain transcription factor, in hepatocellular. However, Nkx2-8-knockout mouse showed the most interesting effects in the lungs, where the mice develop lung cancer starting with expansion of the bronchial stem/progenitor cell population. Thus, Nkx2.8 is a negative regulator that limits the size of the stem/progenitor cell compartment and overexpansion of this compartment promotes bronchial carcinogenesis. Current research focuses on two related areas: the transcriptional target genes of Nkx2-8 and the specific cell fate transitions controlled by these targets. A related human translational project on human lung cancer characterizes suppressor genes within14q13.3, a commonly deleted interval that contains Nkx2-8.
- BS - University of Pittsburgh, 1967
- PhD - University of Chicago, 1974
- MD - University of Chicago, 1975
NIH ResearchView Dr. Locker's NIH RePORT on nih.gov
Selected PublicationsView Dr. Locker's publications on PubMed
- 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.
- Yannam GR, Han B, Setoyama K, Yamamoto T, Ito R, Brooks JM, Guzman-Lepe J, Galambos C, Fong JV, Deutsch M, Quader MA, Yamanouchi Y, Kabarriti R, Mehta K, Soto-Gutierrez A, Roy-Chowdhury J, Locker J, Abe M, Enke CA, Baranowska-Kortylewicz J, Solberg TD, Guha C, Fox IJ. (2014) A non-human primate model of human radiation-induced venocclusive liver disease and hepatocyte injury. Int J Radiat Onc, 88:404-11. PMID: 24315566.
- 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.