Department of Medicine
Channing Laboratories, Room 861
181 Longwood Avenue
Boston, MA 02115
Lab Members: 3 postdoctoral fellows, 3 graduate students
Visit my lab page here.
We study the molecular mechanisms by which human papillomaviruses (HPVs) cause cervical carcinoma, a leading cause of cancer death in women, worldwide. HPVs encode two major oncoproteins, E6 and E7, which are consistently expressed in cervical carcinomas. E6 and E7 lack intrinsic enzymatic activities and transform cells by stimulating cell growth and inactivating tumor suppressor pathways.
Using proteomic approaches, we have identified several novel potential cellular target proteins of the HPV E6 and E7 oncoproteins. We are determining the biological consequences of the association of the viral oncoproteins with these newly identified cellular targets.
Our recent studies have shown that HPV16 E7 expression alters the histone code of the host cellular chromatin by modulating the expression of histone methyl transferases and demethylases. A major focus of our group is to determine the biochemical mechanisms and biological consequences of these alterations.
We have also discovered that the E6 oncoproteins subverts cellular regulatory networks that are involved in sensing the nutritional status of the infected cells and we are determining the biochemical mechanisms and biological consequences of these interactions.
More recently, we have also been harnessing system-biology approaches to arrive at a comprehensive and integrated view of HPV/host cell interactions. We have performed unbiased genetic loss of function screens to identify cellular enzymes that are necessary for proliferation/survival of HPV oncoprotein expressing cells but are dispensable for normal cells and are evaluating these enzymes as potential therapeutic targets. A second, complementing effort has been to globally capture the intersection of viral and host protein “interactome” networks using biochemical techniques and to determine the transcriptional consequences of the dynamic changes of virus/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.
Investigating the biological consequences of association of HPV oncoproteins with novel cellular target proteins
Investigating the mechanisms of HPV oncoprotein induced epigenetic alterations
Investigating HPV oncoprotein induced alterations in cellular nutrient sensing
Baldwin A, Grueneberg DA, Hellner K, Sawyer J, Grace W, Li W, Harlow E, Munger K: Kinase Requirements in Human Cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3, Proc Natl Acad Sci USA 2010; 107: 12463-8.
McLaughlin-Drubin ME, Crum C, Münger K: The Human Papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming, Proc Natl Acad Sci U S A. 2011; 108: 2130-5.
Spangle JM, Gosh-Choudhury N, Munger K: Activation of cap dependent translation by mucosal Human Papillomavirus E6 proteins is dependent on the integrity of the LXXLL binding motif, J. Virol 2012, 86: 7466-72
For a complete listing of publications click here.
Last Update: 8/1/2012