Dr. Linda E. Greenbaum
Assistant Professor, Dept of Medicine, Division of Gastroenterology

Genetics and Gene Regulation Program

Address

600 Clinical Research Building
415 Curie Boulevard
Philadelphia, Pennsylvania 19104-6145

Office tel.: 215 573-1868
Lab tel.: 215-573-1859
Fax: 215 573-2024
E-mail: greenbal@mail.med.upenn.edu

Education

Harvard University, A.B. (Biology),1980

Columbia University College of Physicians and Surgeons, M.D., 1984

Research Interests

• Regulation of liver growth and homeostasis by cytokine, growth and metabolic signaling pathways
• Role of oxidative stress in insulin resistance and liver injury
  

Key words: hepatocytes, gene regulation, fatty liver disease, cytokines, metabolism, oxidative stress, hypoxia, cell cycle

Search PubMed for articles

Description of Research

The Greenbaum laboratory is interested in understanding the molecular mechanisms that govern cell proliferation, metabolism and injury in the mammalian liver.

Major Projects in the laboratory:

1. Transcriptional regulation of DNA licensing replication factors during hepatocyte proliferation
   
   The preneoplastic stage of hepatocellular carcinoma (HCC) development is characterized by increased proliferation and accumulation of structural genomic alterations. Overexpression of DNA licensing proteins has been detected in premalignant lesions suggesting that increased expression of these proteins may be linked to the abnormal re-replication of the genome, leading to the development of genomic instability and HCC. We have recently demonstrated that expression of E2F regulated genes important for licensing of DNA replication is dependent on the bZIP transcription factor, CCAAT enhancer binding protein beta (C/EBPß). We are investigating the mechanism of transcriptional activation of DNA licensing proteins by C/EBPß using genetic and biochemical approaches.
   
   
2. The role of coactivator proteins for coordinating metabolic and growth signals in the liver.
   
   Transcriptional coactivator proteins are recruited to target gene promoters in response to cellular signals and are responsible for the coordinated transcriptional responses to changes in tissue homeostasis. Because coactivators represent “master controllers” of global changes in transcription, these proteins may represent attractive therapeutic targets for modulating changes in expression of genes responsible for specific biological programs such as proliferation or metabolism. We are using location analysis (ChIP-on-chip) to identify transcription targets of coactivators and knockout mice to directly investigate the function of specific coactivators during hepatocyte growth.
   
3. Long-term intermittent hypoxia for the development of nonalcoholic fatty liver disease
   
   Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease characterized by alterations in metabolism, hepatitis, apoptosis, necrosis and perisinusoidal fibrosis which may ultimately lead to cirrhosis requiring liver transplantation. Using mouse models, we are investigating the mechanism by which oxidative stress caused by obstructive sleep apnea commonly found in NAFLD contributes to the development of this disease.
   
4. Transcriptional regulation of microRNAs during the hepatic growth response
   
   MicroRNAs (miRNAs) control physiologic and pathophysiologic processes in various tissues through down-regulation of protein expression by degrading target mRNAs or inhibition of translation. We are currently applying high-throughput methods including expression array and location analysis (ChIP-on-chip) to investigate the regulation and function of microRNAs that are involved in hepatic growth and metabolism.
   

Recent Publications

Mukherjee D, Kaestner KH, Kovalovich KK, Greenbaum LE.?Fas-induced apoptosis in mouse hepatocytes is dependent on C/EBPß. Hepatology. 2001 May;33(5):1166-72. PMID: 11343245

Friedman, J. R., Larris, B., Le, P.P., Peiris, T.H., Arsenlis, A., Schug, J., Tobias, J.W., Kaestner, K.H. and L.E. Greenbaum. Orthogonal analysis of C/EBPß targets in vivo during liver proliferation. Proc. Nat. Acad. Sci., USA, 101:12986-12991, 2004.

Greenbaum, L.E. Cell Cycle Regulation and Hepatocarcinogenesis. Cancer Biology and Therapy, December 3:1200-1207, 2004 (review)

White, P, Brestelli, J.E., Kaestner, K.H. and L.E. Greenbaum. Identification of transcriptional networks during liver regeneration. J. Biol. Chem., 280: 3715-3722, 2005.

Wang, H., Larris, B., Peiris, TH, Zhang, L., Le Lay, J., Gao, Y., Greenbaum, L. C/EBPbeta activates E2F regulated genes in vivo via recruitment of the coactivator CBP/p300 Journal of Biological Chemistry, 2007 Jun 27; Epub ahead of print, PMID: 17599912

Lab

Rotation Projects

Potential rotation projects are available in each of the major research areas ongoing in the laboratory.

Yan Gao, Ph.D. Postdoctoral researcher
Jenny Yan, Research Specialist
Akivaga Tsingalia, Research Specialist
Sara Muse, Rotation student