Syed S. Mujtaba

Biography

Overview

In our laboratory we aim to study gene regulatory events that control functions of transcription factors using the emerging discipline of chemical biology. Towards this enthusiasm of studying transcription factors function in their biological context, we focus on the cellular models that epitomize human health and diseases including metabolic disorders, heart diseases and cancers, as these are the most mystifying diseases, which remain largely incurable. We choose to study these areas with chemical tools, because if we are able to control behavior of diseased cells then with novel and innovative chemical probes, potential therapeutics could emerge directly from these efforts.

 

From the start of life, cells must recognize and respond to diverse environmental and physiological stimuli. To ensure that these responses are proper, gene expression must be tightly regulated. One key system that influences gene activity is transcriptional regulation, which plays a central role in controlling many biological processes including the time-course of development, cell cycle progression, and maintenance of metabolic balance. Transcriptional regulation in eukaryotes is achieved by the concerted actions of RNA polymerase II, transcription factors, cofactors (co-activators plus co-repressors), histones and chromatin remodeling proteins. More recently, it has been shown that epigenetic events occurring in the vicinity of a gene promoter influence gene expression. Unarguably, the elements of transcriptional regulation are integrated into human physiology and during adverse circumstances directly contribute to disease processes. Thus, focus of intense investigation representing potential targets of future drug development.

 

Research Plan

Understand Molecular Interplay by Chromatin and Co-factor(s) for Orchestring Transcriptional Programming by Transcription Factors

 

The biochemical landscape of lysine acetylation has expanded from the nucleus to the cytoplasm. Since the first report in 1997 confirming acetylation of the tumor suppressor protein p53 by a lysine acetyltransferase (KAT), there has been a surge in the identification of new, non-histone targets of KATs. Added to the known substrates of KATs are metabolic enzymes, cytoskeletal proteins, molecular chaperones, ribosomal proteins and nuclear import factors. Emerging studies demonstrate that no fewer than 2000 proteins in any particular cell type are amenable to lysine acetylation. Our analyses of cellular acetylated proteins have facilitated organization of acetylated proteins into functional clusters integral to cell signaling, the stress response, proteolysis, apoptosis, metabolism, and neuronal development. Not to our surprise, these clusters also depict associations of acetylated proteins with human diseases, including cancers and neurodegenerative disorders. Further, these findings not only support lysine acetylation as a widespread cellular phenomenon, but also impel questions to clarify the underlying molecular and cellular mechanisms governing target selectivity by KATs. However, present challenges are to understand the molecular basis for the overlapping roles of KAT-containing co-activators, to differentiate between global versus dynamic acetylation marks, and to elucidate the roles of acetylated proteins in biochemical pathways in response to stimuli.

 

In higher eukaryotes, the transcriptional regulatory system initiates gene expression, and patterns of post-translational modification (PTM) on histones within chromatin provide epigenetic cues to regulate gene expression. Histone-modifying enzymes catalyze PTM marks on histones, such as acetylation, methylation, and phosphorylation that recruit specific ‘effector’ proteins, which initiate molecular events causing activation or silencing of target genes. Some histone modifying enzymes also catalyze the formation of PTM marks on transcription factors such as NF-κB, p53 and on the androgen receptor (AR). Previous studies of mine have demonstrated the role of acetylation-mediated molecular events during transcriptional activation directed by HIV Tat and p53.  Based on above experience, the immediate goal of my research is to understand the acetylation directed AR functions, especially intercept AR/co-activator interactions, and develop novelagents to block AR functions that promote diseases such as prostate cancer.

 

Research Areas

·         To understand underlying molecular mechanisms that control transcriptional programming by a lysine-acetylated transcription factors.

·         In a cellular model of cancer investigate the role of acetylation-directed biochemical pathway as a potential mechanism for cancer pathogenesis.

·         Use small molecules derived from natural products to modulate transcription of disease related genes.

Selected Publications

Emerging role of protein acetylation in pathogenesis of androgen -dependent and -independent PCa. Ravi Pathak, Michael Ohlemeyer and Shiraz Mujtaba. Submitted

 

The Biology of Lysine Acetylation Integrates Transcriptional Programming and Metabolism. Jigneshkumar Patel, Ravi Pathak and Shiraz Mujtaba. Submitted

 

A Small Molecule Binding to the Co-activator CREB-Binding Protein Blocks Apoptosis in Ischemic Cardiomyocytes. Jagat C. Borah*, Shiraz Mujtaba*, Ioannis Karakikes,  Weijia Zhang, Guillermo Gerona-Navarro, Roger J. Hajjar, & Ming-Ming Zhou. * Equal contribution Submitted

 

Mujtaba, S., Manzur, K.L., Gurnoon, J., Kang, M., Van Etten, J.L., and Zhou, M.-M. (2008) Epigenetic transcriptional repression of cellular genes by a viral SET protein. Nature Cell Biology 10, 1114-1122. Accompanying Editorial: Jeremy, A. (2008) Viral pathogenesis: Virus SETs host transcription to off. Nature Reviews Microbiology 6, 713.

 

Pan, C., Mezei, M., Mujtaba, S., Muller, M., Zeng, L., Li, J., Wang, Z., and Zhou, M.-M. (2007)  Structure-guided optimization of small molecules inhibiting HIV-1 Tat association with the human co-activator p300/CREB binding protein-associated factor. Journal of Medicinal Chemistry 17, 2285-2288.

 

Zeng, L., Li, J., Muller, M., Yan, S., Mujtaba, S., Pan, C., Wang, Z., and Zhou, M.-M. (2005) Selective small molecules blocking HIV-1 Tat and co-activator PCAF association. Journal of American Chemical Society 127, 2376-2377.

 

Colleagues in the Laboratory

Ravi Pathak: Post Doctoral Fellow

 

Jignesh Patel: Research Coordinator and Prospective Ph.D Student

 

Collaborators

Mike Ohlmeyer: Associate Professor, Dept of Structural and Chemical Biology