Associate Virologist
Brigham and Women's Hospital

kmunger@rics.bwh.harvard.edu

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 solid tumors.

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.

HPV16 E7 induces proteasome-mediated degradation of the pRB tumor suppressor. Our proteomic analyses have yielded evidence that E7 associates with multiple components of the ubiquitin mediated proteasomal degradation pathway and we are investigating the mechanism of E7-induced pRB degradation. In addition, we aim to identify additional cellular substrates that are targeted for degradation through E7-associated components of the ubiquitin/proteasome pathway.

Genomic destabilization is a key process for cancer development. Expression of HPV16 E6/E7 oncoproteins in primary human epithelial cells causes genomic instability. Expression of E7 gives rise to aberrant synthesis of mitotic spindle pole bodies, centrosomes. This results in formation of multipolar mitotic spindles, which causes chromosome missegregation and aneuploidy. This mitotic mutator function of E7 plays a pivotal role for the carcinogenic progression for HPV-associated lesions and is independent of pRB tumor suppressor inactivation. In addition, E7 expressing cells also exhibit evidence for increased double strand DNA breaks, which causes structural chromosomal aberrations. We are investigating the biochemical bases for these genome-destabilizing activities of HPV oncoproteins.

Eichten A, Rud DS, Grace M, Piboonniyom S, Zacny V, Münger K. Molecular pathways executing the “trophic sentinel” response in HPV-16 E7 expressing normal human diploid fibroblasts upon growth factor deprivation, Virology. 2004 Feb 5;319(1):81-93. [abstract]

Duensing S, Münger K. Mechanisms of genomic instability in human cancer – insights from studies with human papillomavirus oncoproteins. Int J Cancer. 2004 Mar 20;109(2):157-62. Review. [abstract]

Münger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, Owens M, Grace M, Huh KW. Mechanisms of Human Papillomavirus-induced Oncogenesis. J Virol. 2004 Nov;78(21):11451-60. Review. No abstract available.

Duensing S, Duensing A, Lee DC, Edwards KM, Piboonniyom S, Manuel E, Skaltsounis L, Meijer L, Münger K. The cyclin-dependent kinase inhibitor indirubin-3’-oxime selectively inhibits human papillomavirus type 16 E7-induced numerical centrosome anomalies. Oncogene. 2004 Oct 28;23(50):8206-15. [abstract]

Huh K-W, DeMasi J, Ogawa H, Nakatani Y, Howley PM, Münger K. Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600. Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11492-7. Epub 2005 Aug 1. [abstract]

Hasskarl J, Velupillai P, Münger K. Increased in vitro life span of primary human keratinocytes correlates with decreased migration. J Invest Dermatol. 2006 May;126(5):1179-81. No abstract available.

Baldwin A, Huh KW, Münger K. The HPV E7 Oncoprotein Dysregulates Steroid Receptor Coactivator-1 Localization and Function. J Virol. 2006 Jul;80(13):6669-77. [abstract]