Steve McMahon, Ph.D.
Associate Professor, The Wistar Institute

Cancer Biology

Address

Wistar Institute
3601 Spruce Street
Philadelphia, PA 19104-4268

Office tel.: 215 898-3736
Lab tel.: 215 898-3777
Fax: 215 215 898-3933
E-mail: smcmahon@wistar.upenn.edu

Link(s)

Dr McMahon at The Wistar Institute

Education

Albright College, BS (Biology), 1982

Temple University, MS (Biology) 1984

University of Pennsylvania, PhD, (Immunology), 1994.

Princeton University: Postdoctoral Fellow, (Molecular Biology), 1999.

Research Interests

• Transcriptional Regulation and Chromatin Function in Human Cancer

Key words: c-MYC, p53, transcription, chromatin, acetylation, TRRAP, histones.

Search PubMed for articles

Description of Research

The main goal of our work is to understand how the deregulation of transcriptional networks contributes to human cancer. We primarily study the sequence specific transcription factors c MYC and p53. c MYC represents the most commonly over expressed oncoprotein and p53 the most commonly mutated tumor suppressor in human cancer. Both proteins function in part via their ability to regulate the expression of downstream target genes essential for the potent biological activity ascribed to c MYC and p53. What remains only partially understood is the precise biochemical mechanism by which c MYC and p53 regulate transcription. In addition, for c MYC the actual identity of its essential downstream targets remains largely obscure. Our focus on these poorly understood aspects of c MYC and p53 function stems from our discovery several years ago that the c MYC oncoprotein controls gene expression by recruiting a family of histone acetyltransferase (HAT) complexes, a result subsequently confirmed by a number of other groups. These complexes contain a 434 kDa subunit termed TRRAP that directly interacts with c MYC, thereby mediating recruitment of the HAT complexes to specific genetic loci in order to facilitate histone acetylation and transcription. Most importantly, the recruitment of the TRRAP/HAT complexes is essential for cellular transformation by c MYC. The paradigm that our initial work established is that the TRRAP/HAT complexes are critical for c MYC function because they acetylate target gene histones. However, we have now shown that these complexes also regulate c MYC function by an additional, distinct mechanism. In a study published recently, we demonstrated that c MYC itself is substrate of the TRRAP associated acetyltransferases. We further demonstrated that this acetylation has a profound effect on c MYC stability and current studies are aimed at defining the relative contribution of TRRAP/HAT mediated acetylation of histones versus c MYC itself to c MYC function.

Shortly after the discovery of TRRAP/HAT complexes as essential c MYC cofactors it became clear that other human transcription factors utilize these complexes as well. For example, we have now demonstrated that the E2F proteins, p53 and nuclear hormone receptors must recruit these complexes to activate transcription.

Recent Publications

P.G. Ard, S. Kunjibettu, C. Chatterjee, L. Adside, L.E. Gralinski and S.B. McMahon. 2002. Transcriptional regulation of the mdm2 oncogene by p53 involves TRRAP acetyltransferase complexes. Mol. Cell. Biol. 22: 5650 5661.

J.H. Patel, A.P. Loboda, M.K. Showe, L.C. Showe and S.B. McMahon. 2004. Analysis of genomic targets reveals complex functions of MYC. Nature Reviews Cancer 4: 562 568.

J.H. Patel, Y. Du, P.G. Ard, C. Phillips, B. Carella, C.J. Chen, C. Rakowski, C. Chatterjee, P.M. Lieberman, W.S. Lane, G.A. Blobel and S.B. McMahon. 2004. The c MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60. Mol. Cell. Biol. 24: 10826 34.

X. Zhang, J.H. Patel and S.B. McMahon. 2005. c MYC regulates transcription of metastasis associated gene 1 (MTA1) in human breast cancer cells. (in revision PNAS)

X. Zhang, L.M. DeSalle and S.B. McMahon. Identification of the gene encoding the lymphoma antigen CD30 as a TRRAP dependent target of c MYC. (submitted).

Lab

Rotation Projects

1. Define how newly defined targets of c MYC regulate the cellular transformation process. A recent genetic screen in our lab identified a number of novel c MYC targets. The hits characterized to date have provided significant insight into how c MYC regulates specific aspects of cellular transformation. Current efforts are aimed at defining the specific biochemical role played by these targets in the transformation process
2. Determine the non histone substrates of the TRRAP/acetyltransferase complexes. It has become clear in recent years that acetyltransferases have both histone and non histone substrates. Typically the non histone substrates have been identified and characterized on an ad hoc basis, as we have done with c MYC and p53. We have now initiated studies aimed at identifying non histone substrates of specific TRRAP/acetyltransferases complexes using an unbiased proteomics approach
3. Biochemical functions of specific subunits of the TRRAP/HAT complexes. Beyond the TRRAP subunit, which we have shown provides the activator docking surface, and the acetyltransferase subunits (hGCN5, PCAF and TIP60), the majority of subunits within these complexes remain poorly characterized. A thorough understanding of the role played by these complexes in activator driven transcription requires that we completely resolve the function of each of their 10-15 subunits. As an example of our focus in this area, we have identified a novel enzymatic subunit within the human TRRAP/hGCN5 complex. We have shown that this subunit catalyzes the removal of mono ubiquitin from histone H2A, an event required for reversing transcriptional repression. Capitalizing on the knowledge gained in our studies of the c MYC TRRAP/HAT interaction, we have now demonstrated that this novel ubiquitin hydrolase is required for the transcription of TRRAP/HAT dependent targets of c MYC. Using our p53 and c MYC systems as models for activator dependent transcription, we are similarly exploring the function of additional TRRAP/HAT complex subunits.
4. Define the biochemical mechanism by which c MYC represses the transcription of selected targets? It is clear that at least some of the essential downstream targets of c MYC are repressed rather than activated. In studies analogous to those in which we defined the TRRAP/HAT complexes are critical co activators for c MYC, we are currently focused on defining the co repressors used by c MYC to block the transcription of selected target genes

Lab personnel:

Xiao-yong Zhang, PhD Postdoctoral Fellow

Latoya Campbell graduate student

Hyunjin Kim graduate student

Jagruti H. Patel graduate student

Stephen M. Sykes graduate student

Joan Lee Research Assistant