DF/HCC Program Affiliation

Head and Neck Cancer
Cancer Cell Biology

DF/HCC Associations

Member, Web Advisory
Institutional Representative for HMS, Membership Committee

Research Abstract

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 Harvard Medical School 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.

Publications

• Mangold U, Hayakawa H, Coughlin M, Münger K, Zetter BR.Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification.Oncogene 2008 Jan 24;27(5):604-13.
  17667942
• Levitt JM, Baldwin A, Papadakis A, Puri S, Xylas J, Münger K, Georgakoudi I.Intrinsic fluorescence and redox changes associated with apoptosis of primary human epithelial cells.J Biomed Opt 2006 Nov-Dec;11(6):064012.
  17212535
• Baldwin A, Huh KW, Münger K.Human papillomavirus E7 oncoprotein dysregulates steroid receptor coactivator 1 localization and function.J Virol 2006 Jul;80(13):6669-77.
  16775354
• Huh KW, 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.
  16061792
• Ruiz M, Singh P, Thomson SC, Munger K, Blantz RC, Gabbai FB.L-arginine-induced glomerular hyperfiltration response: the roles of insulin and ANG II.Am J Physiol Regul Integr Comp Physiol 2008 May;294(5):R1744-51.
  18353876
• De Jager PL, Simon KC, Munger KL, Rioux JD, Hafler DA, Ascherio A.Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis.Neurology 2008 Mar 25;70(13 Pt 2):1113-8.
  18272866
• Mangold U, Hayakawa H, Coughlin M, Münger K, Zetter BR.Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification.Oncogene;27(5):604-13.
• McLaughlin-Drubin ME, Munger K.Viruses associated with human cancer.Biochim Biophys Acta 2008 Mar;1782(3):127-50.
  18201576
• Mujat C, Greiner C, Baldwin A, Levitt JM, Tian F, Stucenski LA, Hunter M, Kim YL, Backman V, Feld M, Munger K, Georgakoudi I.Endogenous optical biomarkers of normal and human papillomavirus immortalized epithelial cells.Int J Cancer 2008 Jan 15;122(2):363
  17935126
• Nguyen CL, Eichwald C, Nibert ML, Münger K.Human papillomavirus type 16 E7 oncoprotein associates with the centrosomal component gamma-tubulin.J Virol 2007 Dec;81(24):13533-43.
  17913829
• Simon K, Yang X, Munger K, Ascherio A.Variation in the Epstein-Barr virus receptor, CR2, and risk of multiple sclerosis.Mult Scler 2007 Aug;13(7):947-8.
  17881405
• Huh K, Zhou X, Hayakawa H, Cho JY, Libermann TA, Jin J, Wade Harper J, Munger K.Human papillomavirus type 16 e7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor.J Vi
  17609271
• Georgakoudi I, Levitt J, Baldwin A, Papadakis A, Münger K.Intrinsic fluorescence changes associated with apoptosis of human epithelial keratinocytes.Gynecol Oncol 2005 Dec;99(3 Suppl 1):S54-7.
  16419185
• Münger K, Hayakawa H, Nguyen CL, Melquiot NV, Duensing A, Duensing S.Viral carcinogenesis and genomic instability.EXS 2006(96):179-99.
  16383019
• DeMasi J, Huh KW, Nakatani Y, Münger K, Howley PM.Bovine papillomavirus E7 transformation function correlates with cellular p600 protein binding.Proc Natl Acad Sci U S A 2005 Aug 9;102(32):11486-91.
  16081543
• Hasskarl J, Velupillai P, Piboonniyom SO, Grace M, Münger K.Long-term maintenance of human keratinocytes in vitro.J Invest Dermatol 2005 Feb;124(2):475-8.
  15675970
• Tarunina M, Alger L, Chu G, Munger K, Gudkov A, Jat PS.Functional genetic screen for genes involved in senescence: role of Tid1, a homologue of the Drosophila tumor suppressor l(2)tid, in senescence and cell survival.Mol Cell Biol 2004 Dec;24(24):10792-80
  15572682
• Münger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, Owens M, Grace M, Huh K.Mechanisms of human papillomavirus-induced oncogenesis.J Virol 2004 Nov;78(21):11451-60.
  15479788
• Duensing S, Duensing A, Lee DC, Edwards KM, Piboonniyom SO, Manuel E, Skaltsounis L, Meijer L, Münger K.Cyclin-dependent kinase inhibitor indirubin-3'-oxime selectively inhibits human papillomavirus type 16 E7-induced numerical centrosome anomalies.Oncoge
  15378001
• Edwards KM, Münger K.Depletion of physiological levels of the human TID1 protein renders cancer cell lines resistant to apoptosis mediated by multiple exogenous stimuli.Oncogene 2004 Nov 4;23(52):8419-31.
  15156195
• Edwards KM, Münger K.Make WARTS, not cancer!.Oncogene 2004 Jul 8;23(31):5263-5.
  15122320
• Badizadegan K, Backman V, Boone CW, Crum CP, Dasari RR, Georgakoudi I, Keefe K, Munger K, Shapshay SM, Sheetse EE, Feld MS.Spectroscopic diagnosis and imaging of invisible pre-cancer.Faraday Discuss 2004;126:265-79; discussion 303-11.
  14992412
• Eichten A, Rud DS, Grace M, Piboonniyom SO, 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.
  14967490
• Hasskarl J, Duensing S, Manuel E, Münger K.The helix-loop-helix protein ID1 localizes to centrosomes and rapidly induces abnormal centrosome numbers.Oncogene 2004 Mar 11;23(10):1930-8.
  14755252
• 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.
  14750163
• Balsitis SJ, Sage J, Duensing S, Münger K, Jacks T, Lambert PF.Recapitulation of the effects of the human papillomavirus type 16 E7 oncogene on mouse epithelium by somatic Rb deletion and detection of pRb-independent effects of E7 in vivo.Mol Cell Biol 20
  14645521
• Duensing S, Münger K.Centrosome abnormalities and genomic instability induced by human papillomavirus oncoproteins.Prog Cell Cycle Res 2003;5:383-91.
  14593733
• Duensing S, Münger K.Human papillomavirus type 16 E7 oncoprotein can induce abnormal centrosome duplication through a mechanism independent of inactivation of retinoblastoma protein family members.J Virol 2003 Nov;77(22):12331-5.
  14581569
• Kleine-Lowinski K, Rheinwald JG, Fichorova RN, Anderson DJ, Basile J, Münger K, Daly CM, Rösl F, Rollins BJ.Selective suppression of monocyte chemoattractant protein-1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial
  14506741
• Duensing S, Lee BH, Dal Cin P, Münger K.Excessive centrosome abnormalities without ongoing numerical chromosome instability in a Burkitt's lymphoma.Mol Cancer 2003 Sep 8;2(1):30.
  14498992
• Riley RR, Duensing S, Brake T, Münger K, Lambert PF, Arbeit JM.Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis.Cancer Res 2003 Aug 15;63(16):4862-71.
  12941807
• Syken J, Macian F, Agarwal S, Rao A, Münger K.TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells.Oncogene 2003 Jul 24;22(30):4636-41.
  12879007
• Duensing S, Münger K.Centrosomes, genomic instability, and cervical carcinogenesis.Crit Rev Eukaryot Gene Expr 2003;13(1):9-23.
  12839094
• Basile JR, Eichten A, Zacny V, Münger K.NF-kappaB-Mediated Induction of p21(Cip1/Waf1) by Tumor Necrosis Factor alpha Induces Growth Arrest and Cytoprotection in Normal Human Keratinocytes.Mol Cancer Res 2003 Feb;1(4):262-70.
  12612054
• Genther SM, Sterling S, Duensing S, Münger K, Sattler C, Lambert PF.Quantitative role of the human papillomavirus type 16 E5 gene during the productive stage of the viral life cycle.J Virol 2003 Mar;77(5):2832-42.
  12584306
• Piboonniyom SO, Duensing S, Swilling NW, Hasskarl J, Hinds PW, Münger K.Abrogation of the retinoblastoma tumor suppressor checkpoint during keratinocyte immortalization is not sufficient for induction of centrosome-mediated genomic instability.Cancer Res
  12543805
• Duensing S, Münger K.The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability.Cancer Res 2002 Dec 1;62(23):7075-82.
  12460929
• Eichten A, Westfall M, Pietenpol JA, Münger K.Stabilization and functional impairment of the tumor suppressor p53 by the human papillomavirus type 16 E7 oncoprotein.Virology 2002 Mar 30;295(1):74-85.
  12033767
• Piboonniyom SO, Timmermann S, Hinds P, Münger K.Aberrations in the MTS1 tumor suppressor locus in oral squamous cell carcinoma lines preferentially affect the INK4A gene and result in increased cdk6 activity.Oral Oncol 2002 Feb;38(2):179-86.
  11854066
• Münger K, Basile JR, Duensing S, Eichten A, Gonzalez SL, Grace M, Zacny VL.Biological activities and molecular targets of the human papillomavirus E7 oncoprotein.Oncogene 2001 Nov 26;20(54):7888-98.
  11753671
• Jiang X, Wilford C, Duensing S, Munger K, Jones G, Jones D.Participation of Survivin in mitotic and apoptotic activities of normal and tumor-derived cells.J Cell Biochem 2001 Aug 1-9;83(2):342-54.
  11573250
• Duensing S, Duensing A, Flores ER, Do A, Lambert PF, Münger K.Centrosome abnormalities and genomic instability by episomal expression of human papillomavirus type 16 in raft cultures of human keratinocytes.J Virol 2001 Aug;75(16):7712-6.
  11462043
• Gonzalez SL, Stremlau M, He X, Basile JR, Münger K.Degradation of the retinoblastoma tumor suppressor by the human papillomavirus type 16 E7 oncoprotein is important for functional inactivation and is separable from proteasomal degradation of E7.J Virol 2
  11462030
• Thompson DA, Zacny V, Belinsky GS, Classon M, Jones DL, Schlegel R, Münger K.The HPV E7 oncoprotein inhibits tumor necrosis factor alpha-mediated apoptosis in normal human fibroblasts.Oncogene 2001 Jun 21;20(28):3629-40.
  11439326
• Keating JT, Cviko A, Riethdorf S, Riethdorf L, Quade BJ, Sun D, Duensing S, Sheets EE, Munger K, Crum CP.Ki-67, cyclin E, and p16INK4 are complimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia.Am J Surg Pathol 2001 Jul;25(
  11420459
• Duensing S, Münger K.Centrosome abnormalities, genomic instability and carcinogenic progression.Biochim Biophys Acta 2001;1471(2):M81-8.
  11342187
• Basile JR, Zacny V, Münger K.The cytokines tumor necrosis factor-alpha (TNF-alpha ) and TNF-related apoptosis-inducing ligand differentially modulate proliferation and apoptotic pathways in human keratinocytes expressing the human papillomavirus-16 E7 onc
  11306566
• Duensing S, Duensing A, Crum CP, Münger K.Human papillomavirus type 16 E7 oncoprotein-induced abnormal centrosome synthesis is an early event in the evolving malignant phenotype.Cancer Res 2001 Mar 15;61(6):2356-60.
  11289095
• Münger K.Learning old tricks from new viruses.Nat Med 2000 Oct;6(10):1091-2.
  11017130
• Duensing S, Lee LY, Duensing A, Basile J, Piboonniyom S, Gonzalez S, Crum CP, Munger K.The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell d
  10944189
• Wong DT, Münger K.Association of human papillomaviruses with a subgroup of head and neck squamous cell carcinomas.J Natl Cancer Inst 2000 May 3;92(9):675-7.
  10793095
• Oettgen P, Kas K, Dube A, Gu X, Grall F, Thamrongsak U, Akbarali Y, Finger E, Boltax J, Endress G, Munger K, Kunsch C, Libermann TA.Characterization of ESE-2, a novel ESE-1-related Ets transcription factor that is restricted to glandular epithelium and di
  10506207
• Alani RM, Hasskarl J, Grace M, Hernandez MC, Israel MA, Münger K.Immortalization of primary human keratinocytes by the helix-loop-helix protein, Id-1.Proc Natl Acad Sci U S A 1999 Aug 17;96(17):9637-41.
  10449746
• Timmermann S, Hinds PW, Münger K.Re-expression of endogenous p16ink4a in oral squamous cell carcinoma lines by 5-aza-2'-deoxycytidine treatment induces a senescence-like state.Oncogene 1998 Dec 31;17(26):3445-53.
  10030668
• Alani RM, Hasskarl J, Münger K.Alterations in cyclin-dependent kinase 2 function during differentiation of primary human keratinocytes.Mol Carcinog 1998 Dec;23(4):226-33.
  9869451
• Schilling B, De-Medina T, Syken J, Vidal M, Münger K.A novel human DnaJ protein, hTid-1, a homolog of the Drosophila tumor suppressor protein Tid56, can interact with the human papillomavirus type 16 E7 oncoprotein.Virology 1998 Jul 20;247(1):74-85.
  9683573
• Mavromatis KO, Jones DL, Mukherjee R, Yee C, Grace M, Münger K.The carboxyl-terminal zinc-binding domain of the human papillomavirus E7 protein can be functionally replaced by the homologous sequences of the E6 protein.Virus Res 1997 Nov;52(1):109-18.
  9453149
• Thompson DA, Belinsky G, Chang TH, Jones DL, Schlegel R, Münger K.The human papillomavirus-16 E6 oncoprotein decreases the vigilance of mitotic checkpoints.Oncogene 1997 Dec 18;15(25):3025-35.
  9444951
• Jones DL, Thompson DA, Münger K.Destabilization of the RB tumor suppressor protein and stabilization of p53 contribute to HPV type 16 E7-induced apoptosis.Virology 1997 Dec 8;239(1):97-107.
  9426450
• Jones DL, Alani RM, Münger K.The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2.Genes Dev 1997 Aug 15;11(16):2101-11.
  9284049
• Jones DL, Münger K.Analysis of the p53-mediated G1 growth arrest pathway in cells expressing the human papillomavirus type 16 E7 oncoprotein.J Virol 1997 Apr;71(4):2905-12.
  9060648
• Timmermann S, Hinds PW, Münger K.Elevated activity of cyclin-dependent kinase 6 in human squamous cell carcinoma lines.Cell Growth Differ 1997 Apr;8(4):361-70.
  9101082
• Clemens KE, Brent R, Gyuris J, Münger K.Dimerization of the human papillomavirus E7 oncoprotein in vivo.Virology 1995 Dec 1;214(1):289-93.
  8525630
• Brokaw JL, Yee CL, Münger K.A mutational analysis of the amino terminal domain of the human papillomavirus type 16 E7 oncoprotein.Virology 1994 Dec;205(2):603-7.
  7975265
• Arbeit JM, Münger K, Howley PM, Hanahan D.Progressive squamous epithelial neoplasia in K14-human papillomavirus type 16 transgenic mice.J Virol 1994 Jul;68(7):4358-68.
  7515971
• Münger K, Phelps WC.The human papillomavirus E7 protein as a transforming and transactivating factor.Biochim Biophys Acta 1993 May 25;1155(1):111-23.
  8389201
• Arbeit JM, Münger K, Howley PM, Hanahan D.Neuroepithelial carcinomas in mice transgenic with human papillomavirus type 16 E6/E7 ORFs.Am J Pathol 1993 Apr;142(4):1187-97.
  8386443