Karl Munger, Ph.D.
Associate Professor of Medicine
Brigham & Women's Hospital, Channing Labs
181 Longwood Avenue, Room 861
Boston, MA 02115-5701
6 postdoctoral fellows, 1 graduate students
High-risk human papillomaviruses (HPVs) are causally associated with the development of cervical cancers, a leading cause of cancer death in young women worldwide. Greater that 99% of all human cervical carcinomas are high-risk HPV positive and express the HPV E6 and E7 oncoproteins. Sustained HPV E6/E7 expression is necessary for maintenance of the transformed state. The Münger Lab uses HPV oncoproteins, particularly E7, as tools to discover cellular regulatory pathways that are targeted during development of human cancers.
We have performed an extensive proteomic analysis of HPV16 E7 associated host cellular protein complexes. In addition to known cellular targets of E7, which include the retinoblastoma tumor suppressor pRB, we identified a large number of novel potential targets of the HPV E7 oncoprotein. We are determining the biochemical parameters and biological consequences of E7’s association with these novel cellular targets. As a first step towards globally investigating HPV/host cell interactions, we collaborate with Ed Harlow’s group at the Harvard Institute of Proteomics (HIP) to identify protein kinases that exhibit a “synthetic lethal” phenotype in cervical carcinoma cells. The hypothesis of these studies is that HPV oncogene expression in a normal human epithelial cell causes significant physiological alterations (“oncogene addiction”) that can be exploited to identify specific synthetic lethal phenotypes and that we will be able to assign these phenotypes to specific activities of the HPV oncoproteins. A second, complementing effort is to globally capture the biochemical intersection of viral and host protein “interactome” networks using yeast genetic and biochemical techniques and to determine the transcriptional consequences of the dynamic changes of virus/host cell interactions. This work is done in collaboration with Marc Vidal at the Dana Farber Cancer Institute. These studies will allow us to integrate the data sets with genetic mapping information, predicted and established gene functional role classifications and metabolic pathway assignments, phenotypic classifications, metabolic profiling patterns, and clinical data and holds the promise to arrive at a comprehensive and integrated view of HPV/host cell interactions.
Genomic destabilization is a key process for cancer development. Expression of HPV16 E6/E7 oncoproteins in primary human epithelial cells causes genomic instability. We are investigating the biochemical bases for these genome-destabilizing activities of HPV oncoproteins.
Biological consequences of association of HPV oncoproteins with novel cellular targets
Biochemistry of HPV oncoprotein mediated genomic destabilization.
- Baldwin A, Li W, Grace M, Pearlberg J, Harlow E, Münger K, Grueneberg DA: Kinase Requirements in Human Cells: II. Genetic Interaction Screens Identify Kinase Requirements Following HPV16 E7 Expression in Cancer Cells. Proc Natl Acad Sci USA 2008;105:16478-83
- Nguyen CL, McLaughlin-Drubin ME, Münger K: Delocalization of the Microtubule Motor Dynein from Mitotic Spindles by the Human Papillomavirus E7 Oncoprotein is Not Sufficient for Induction of Multipolar Mitoses. Cancer Res 2008;68:8715-22
- Nguyen CL, Munger, K: The human papillomavirus E7 protein deregulates mitosis via an association with the Nuclear Mitotic Apparatus Protein-1 (NuMA), J Virol 2009;83:1700-7
Virology webpage updated 12/02/2009