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Mitchell Denning
Primary Department
Joint Department
Molecular Pharmacology and Therapeutics
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Advanced Degrees
University of Wisconsin, Madison , Madison , WI , United States
Non-melanoma skin cancers (basal and squamous cell carcinomas) are the most common type of human cancer. Dr. Denning's laboratory studies signaling pathways which regulate normal skin homeostasis to better understand how alterations in these signaling pathways contribute to malignancy. They are focusing on the involvement of the protein kinase C (PKC) family of enzymes in the multi-step transformation of human keratinocytes. PKC is a central regulator of the normal keratinocyte differentiation program, and alterations in epidermal differentiation and PKC signaling are evident in malignant keratinocytes as well as a large number of benign skin diseases. PKC is directly activated by phorbol ester tumor promoters commonly used in mouse skin chemical carcinogenesis studies. Dr. Denning's lab discovered that PKC is also activated by ultraviolet radiation, the main environmental carcinogen for human skin cancer formation. They are using a variety of cell biological, biochemical, pharmacological, and molecular genetic approaches to characterize the functional significance of PKC activation in normal and neoplastic keratinocytes. Their long-term goals are to target these signaling pathways for therapeutic or preventive interventions in skin cancer.
Cell cycles
Growth Factors
Signal Transduction
Skin Diseases
Tissue Engineering
Transgenic Animals
UV Radiation
Reactive Oxygen Species
Recombinant DNA
Haick,J. M.; Brueggemann,L. I.; Cribbs,L. L.; Denning,M. F.; Schwartz,J.; Byron,K. L.PKC-dependent regulation of Kv7.5 channels by the bronchoconstrictor histamine in human airway smooth muscle cells American journal of physiology.Lung cellular and molecular physiology 2017 ;312(6):L822-L834
Arteaga,M.; Shang,N.; Ding,X.; Yong,S.; Cotler,S. J.; Denning,M. F.; Shimamura,T.; Breslin,P.; Luscher,B.; Qiu,W.Inhibition of SIRT2 suppresses hepatic fibrosis American journal of physiology.Gastrointestinal and liver physiology 2016 ;310(11):G1155-68
Ha,G. H.; Kim,J. L.; Petersson,A.; Oh,S.; Denning,M. F.; Patel,T.; Breuer,E. K.TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition Oncogene 2015 ;34(13):1667-1678
Kim,J. L.; Ha,G. H.; Campo,L.; Denning,M. F.; Patel,T. B.; Osipo,C.; Lin,S. Y.; Breuer,E. K.The role of Rak in the regulation of stability and function of BRCA1 Oncotarget 2015 ; :
Fenton,S. E.; Denning,M. F.FYNagling divergent adhesive functions for Fyn in keratinocytes Experimental dermatology 2015 ;24(2):81-85
Fenton,S. E.; Hutchens,K. A.; Denning,M. F.Targeting Fyn in Ras-transformed cells induces F-actin to promote adherens junction-mediated cell-cell adhesion Molecular carcinogenesis 2015 ;54(10):1181-1193
Driver,J.; Weber,C. E.; Callaci,J. J.; Kothari,A. N.; Zapf,M. A.; Roper,P. M.; Borys,D.; Franzen,C. A.; Gupta,G. N.; Wai,P. Y.; Zhang,J.; Denning,M. F.; Kuo,P. C.; Mi,Z.Alcohol inhibits osteopontin-dependent transforming growth factor-beta1 expression in human mesenchymal stem cells The Journal of biological chemistry 2015 ;290(16):9959-9973
Pandya,K.; Wyatt,D.; Gallagher,B.; Shah,D.; Baker,A.; Bloodworth,J.; Zlobin,A.; Pannuti,A.; Green,A.; Ellis,I. O.; Filipovic,A.; Sagert,J.; Rana,A.; Albain,K. S.; Miele,L.; Denning,M. F.; Osipo,C.PKCalpha Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance Clinical cancer research : an official journal of the American Association for Cancer Research 2015 ; :
Zhang,H.; Lin,Y.; Manas,A.; Zhao,Y.; Denning,M. F.; Ma,L.; Xiang,J.BaxDelta2 promotes apoptosis through caspase-8 activation in microsatellite-unstable colon cancer Molecular cancer research : MCR 2014 ;12(9):1225-1232
Wheeler,D. L.; Verma,A. K.; Denning,M. F.Mouse models of the skin: models to define mechanisms of skin carcinogenesis Journal of skin cancer 2013 ;2013:971495
Yun,J.; Pannuti,A.; Espinoza,I.; Zhu,H.; Hicks,C.; Zhu,X.; Caskey,M.; Rizzo,P.; D'Souza,G.; Backus,K.; Denning,M. F.; Coon,J.; Sun,M.; Bresnick,E. H.; Osipo,C.; Wu,J.; Strack,P. R.; Tonetti,D. A.; Miele,L.Crosstalk between PKCalpha and Notch-4 in endocrine-resistant breast cancer cells Oncogenesis 2013 ;2:e60
Denning,M. F.Specifying protein kinase C functions in melanoma Pigment Cell & Melanoma Research 2012 ;25(4):466-476
Donovan,A. J.; Lansu,K.; Williams,J. G.; Denning,M. F.; Gentile,S.Long QT2 mutation on the Kv11.1 ion channel inhibits current activity by ablating a protein kinase Calpha consensus site Molecular pharmacology 2012 ;82(3):428-437
Mascia,F.; Denning,M.; Kopan,R.; Yuspa,S. H.The black box illuminated: signals and signaling The Journal of investigative dermatology 2012 ;132(3 Pt 2):811-819
Hobbs,R. P.; Amargo,E. V.; Somasundaram,A.; Simpson,C. L.; Prakriya,M.; Denning,M. F.; Green,K. J.The calcium ATPase SERCA2 regulates desmoplakin dynamics and intercellular adhesive strength through modulation of PKCα signaling The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2011 ;25(3):990-1001
Yadav,V.; Denning,M. F.Fyn is induced by Ras/PI3K/Akt signaling and is required for enhanced invasion/migration. Molecular carcinogenesis 2011 ;50(5):346-352
Yadav,V.; Yanez,N. C.; Fenton,S. E.; Denning,M. F.Loss of protein kinase C delta gene expression in human squamous cell carcinomas: a laser capture microdissection study. American Journal of Pathology 2010 ;176(3):1091-1096
LaGory,E. L.; Sitailo,L. A.; Denning,M. F.The protein kinase Cdelta catalytic fragment is critical for maintenance of the G2/M DNA damage checkpoint. Journal of Biological Chemistry 2010 ;285(3):1879-1887
Voris,J. P.; Sitailo,L. A.; Rahn,H. R.; Defnet,A.; Gerds,A. T.; Sprague,R.; Yadav,V.; Le Poole,I. C.; Denning,M. F.Functional alterations in protein kinase C beta II expression in melanoma. Pigment Cell & Melanoma Research 2010 ;23(2):216-224
Denning,M. F.Protein kinase C/mitogen-activated protein kinase signaling in keratinocyte differentiation control. Journal of Investigative Dermatology 2010 ;130(8):1968-1970
Denning,M. F.Sun-sensitizing effects of PKCepsilon shine on multiple mouse strains. Journal of Investigative Dermatology 2010 ;130(1):17-19
Sitailo,L. A.; Jerome-Morais,A.; Denning,M. F.Mcl-1 functions as major epidermal survival protein required for proper keratinocyte differentiation. Journal of Investigative Dermatology 2009 ;129(6):1351-1360
Brown,M. V.; Burnett,P. E.; Denning,M. F.; Reynolds,A. B.PDGF receptor activation induces p120-catenin phosphorylation at serine 879 via a PKCalpha-dependent pathway Experimental cell research 2009 ;315(1):39-49
Jerome-Morais,A.; Rahn,H. R.; Tibudan,S. S.; Denning,M. F.Role for protein kinase C-alpha in keratinocyte growth arrest Journal of Investigative Dermatology 2009 ;129(10):2365-2375
Yang,G.; Li,Y.; Nishimura,E. K.; Xin,H.; Zhou,A.; Guo,Y.; Dong,L.; Denning,M. F.; Nickoloff,B. J.; Cui,R.Inhibition of PAX3 by TGF-beta modulates melanocyte viability. Molecular cell 2008 ;32(4):554-563
Bass-Zubek,A. E.; Hobbs,R. P.; Amargo,E. V.; Garcia,N. J.; Hsieh,S. N.; Chen,X.; Wahl,J. K.,3rd; Denning,M. F.; Green,K. J.Plakophilin 2: a critical scaffold for PKC alpha that regulates intercellular junction assembly. Journal of Cell Biology 2008 ;181(4):605-613
Denning,M. F.Tightening the epidermal barrier with atypical PKCs Journal of Investigative Dermatology 2007 ;127(4):742-744
Breitkreutz,D.; Braiman-Wiksman,L.; Daum,N.; Denning,M. F.; Tennenbaum,T.Protein kinase C family: on the crossroads of cell signaling in skin and tumor epithelium Journal of Cancer Research & Clinical Oncology 2007 ;133(11):793-808
Guo,H.; Miao,H.; Gerber,L.; Singh,J.; Denning,M. F.; Gilliam,A. C.; Wang,B.Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer research 2006 ;66(14):7050-7058
Qin,J. Z.; Xin,H.; Sitailo,L. A.; Denning,M. F.; Nickoloff,B. J.Enhanced killing of melanoma cells by simultaneously targeting Mcl-1 and NOXA. Cancer research 2006 ;66(19):9636-9645
D'Costa,A. M.; Robinson,J. K.; Maududi,T.; Chaturvedi,V.; Nickoloff,B. J.; Denning,M. F.The proapoptotic tumor suppressor protein kinase C-delta is lost in human squamous cell carcinomas. Oncogene 2006 ;25(3):378-386
Fan,J.; Guan,S.; Cheng,C. F.; Cho,M.; Fields,J. W.; Chen,M.; Denning,M. F.; Woodley,D. T.; Li,W.PKCdelta clustering at the leading edge and mediating growth factor-enhanced, but not ecm-initiated, dermal fibroblast migration. Journal of Investigative Dermatology 2006 ;126(6):1233-1243
Sitailo,L. A.; Tibudan,S. S.; Denning,M. F.The protein kinase C delta catalytic fragment targets Mcl-1 for degradation to trigger apoptosis. Journal of Biological Chemistry 2006 ;281(40):29703-29710
Chaturvedi,V.; Sitailo,L. A.; Bodner,B.; Denning,M. F.; Nickoloff,B. J.Defining the caspase-containing apoptotic machinery contributing to cornification in human epidermal equivalents. Experimental dermatology 2006 ;15(1):14-22
Alkan,S.; Huang,Q.; Ergin,M.; Denning,M. F.; Nand,S.; Maududi,T.; Paner,G. P.; Ozpuyan,F.; Izban,K. F.Survival role of protein kinase C (PKC) in chronic lymphocytic leukemia and determination of isoform expression pattern and genes altered by PKC inhibition. American Journal of Hematology 2005 ;79(2):97-106
Chaturvedi,V.; Sitailo,L. A.; Qin,J. Z.; Bodner,B.; Denning,M. F.; Curry,J.; Zhang,W.; Brash,D.; Nickoloff,B. J.Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-x(L) reduction thereby enhancing UV-light induced apoptosis. Oncogene 2005 ;24(34):5299-5312
D'Costa,A. M.; Denning,M. F.A caspase-resistant mutant of PKC-delta protects keratinocytes from UV-induced apoptosis. Cell Death & Differentiation 2005 ;12(3):224-232
Sitailo,L. A.; Tibudan,S. S.; Denning,M. F.Bax activation and induction of apoptosis in human keratinocytes by the protein kinase C delta catalytic domain. Journal of Investigative Dermatology 2004 ;123(3):434-443
Qin,J. Z.; Bacon,P.; Panella,J.; Sitailo,L. A.; Denning,M. F.; Nickoloff,B. J.Low-dose UV-radiation sensitizes keratinocytes to TRAIL-induced apoptosis. Journal of cellular physiology 2004 ;200(1):155-166
Denning,M. F.Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoforms International Journal of Biochemistry & Cell Biology 2004 ;36(7):1141-1146
Chaturvedi,V.; Bonish,B.; Bacon,P.; Qin,J. Z.; Denning,M. F.; Foreman,K. E.; Diaz,M. O.; Robinson,J.; Nickoloff,B. J.Role for Id-1 in immunobiology of normal keratinocytes and in basal cell carcinoma. Experimental dermatology 2003 ;12(3):255-260
Ni,H.; Ergin,M.; Tibudan,S. S.; Denning,M. F.; Izban,K. F.; Alkan,S.Protein kinase C-delta is commonly expressed in multiple myeloma cells and its downregulation by rottlerin causes apoptosis. British journal of haematology 2003 ;121(6):849-856
Qin,J. Z.; Chaturvedi,V.; Denning,M. F.; Bacon,P.; Panella,J.; Choubey,D.; Nickoloff,B. J.Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes Oncogene 2002 ;21(19):2991-3002
Sitailo,L. A.; Tibudan,S. S.; Denning,M. F.Activation of caspase-9 is required for UV-induced apoptosis of human keratinocytes The Journal of biological chemistry 2002 ;277(22):19346-19352
Denning,M. F.; Wang,Y.; Tibudan,S.; Alkan,S.; Nickoloff,B. J.; Qin,J. Z.Caspase activation and disruption of mitochondrial membrane potential during UV radiation-induced apoptosis of human keratinocytes requires activation of protein kinase C Cell death and differentiation 2002 ;9(1):40-52
Weinberg,W. C.; Denning,M. F.P21Waf1 control of epithelial cell cycle and cell fate Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists 2002 ;13(6):453-464
Tibudan,S. S.; Wang,Y.; Denning,M. F.Activation of protein kinase C triggers irreversible cell cycle withdrawal in human keratinocytes The Journal of investigative dermatology 2002 ;119(6):1282-1289
Nickoloff,B. J.; Qin,J. Z.; Chaturvedi,V.; Bacon,P.; Panella,J.; Denning,M. F.Life and death signaling pathways contributing to skin cancer The journal of investigative dermatology.Symposium proceedings / the Society for Investigative Dermatology, Inc.[and] European Society for Dermatological Research 2002 ;7(1):27-35
Nickoloff,B. J.; Qin,J. Z.; Chaturvedi,V.; Denning,M. F.; Bonish,B.; Miele,L.Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma Cell death and differentiation 2002 ;9(8):842-855
Park,G. T.; Denning,M. F.; Morasso,M. I.Phosphorylation of murine homeodomain protein Dlx3 by protein kinase C FEBS letters 2001 ;496(1):60-65
Ergin,M.; Denning,M. F.; Izban,K. F.; Amin,H. M.; Martinez,R. L.; Saeed,S.; Alkan,S.Inhibition of tyrosine kinase activity induces caspase-dependent apoptosis in anaplastic large cell lymphoma with NPM-ALK (p80) fusion protein Experimental hematology 2001 ;29(9):1082-1090
Chaturvedi,V.; Qin,J. Z.; Denning,M. F.; Choubey,D.; Diaz,M. O.; Nickoloff,B. J.Abnormal NF-kappaB signaling pathway with enhanced susceptibility to apoptosis in immortalized keratinocytes Journal of dermatological science 2001 ;26(1):67-78
Alt,A.; Ohba,M.; Li,L.; Gartsbein,M.; Belanger,A.; Denning,M. F.; Kuroki,T.; Yuspa,S. H.; Tennenbaum,T.Protein kinase Cdelta-mediated phosphorylation of alpha6beta4 is associated with reduced integrin localization to the hemidesmosome and decreased keratinocyte attachment Cancer research 2001 ;61(11):4591-4598
Amin,H. M.; Ergin,M.; Denning,M. F.; Quevedo,M. E.; Alkan,S.Characterization of apoptosis induced by protein kinase C inhibitors and its modulation by the caspase pathway in acute promyelocytic leukaemia British journal of haematology 2000 ;110(3):552-562
Denning,M. F.; Dlugosz,A. A.; Cheng,C.; Dempsey,P. J.; Coffey,R. J.,Jr; Threadgill,D. W.; Magnuson,T.; Yuspa,S. H.Cross-talk between epidermal growth factor receptor and protein kinase C during calcium-induced differentiation of keratinocytes Experimental dermatology 2000 ;9(3):192-199
Nickoloff,B. J.; Chaturvedi,V.; Bacon,P.; Qin,J. Z.; Denning,M. F.; Diaz,M. O.Id-1 delays senescence but does not immortalize keratinocytes The Journal of biological chemistry 2000 ;275(36):27501-27504