Mitchell Denning
  • Professor
  • Pathology
  • Molecular Pharmacology and Therapeutics
Research Keywords
  • Apoptosis
  • Cancer/Carcinogenesis
  • Cell cycles
  • Epidermis
  • Gene Cloning
  • Growth Factors
  • Retrovirus
  • Signal Transduction
  • Skin Diseases
  • Tissue Engineering
  • Transgenic Animals
  • UV Radiation
  • Immunochemistry
  • Immunofluorescence
  • Immunoprecipitation
  • Melanoma
  • Reactive Oxygen Species
  • Recombinant DNA
Research Summary

Role of protein kinase C isoforms in normal skin biology, the response of skin to ultraviolet radiation, and skin carcinogenesis

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. They recently demonstrated 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. They are also examining the involvement of PKC activation in cell cycle withdrawal (G0) during normal keratinocyte differentiation. Their long-term goals are to target these signaling pathways for therapeutic or preventive interventions in skin cancer. viruses, interaction of the major Simian Virus 40 (SV40) oncogenes with cellular proteins, pathogenesis of mesothelioma.


Alcohol Inhibits Osteopontin Dependent Transforming Growth Factor-beta1 Expression in Human Mesenchymal Stem CellsDriver,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.The Journal of biological chemistry 2015 ; ( ):

Baxdelta2 Promotes Apoptosis through Caspase-8 Activation in Microsatellite Unstable Colon CancerZhang,H.; Lin,Y.; Manas,A.; Zhao,Y.; Denning,M. F.; Ma,L.; Xiang,J.Molecular cancer research : MCR 2014 ; ( ):

TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibitionHa,G. H.; Kim,J. L.; Petersson,A.; Oh,S.; Denning,M. F.; Patel,T.; Breuer,E. K.Oncogene 2014( ):10.1038/onc.2014.105

FYNagling Divergent Adhesive Functions for Fyn in KeratinocytesFenton,S. E.; Denning,M. F.Experimental dermatology 2014 ; ( ):

Targeting Fyn in Ras-transformed cells induces F-actin to promote adherens junction-mediated cell-cell adhesionFenton,S. E.; Hutchens,K. A.; Denning,M. F.Molecular carcinogenesis 2014 ; ( ):

Crosstalk between PKCalpha and Notch-4 in endocrine-resistant breast cancer cellsYun,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.Oncogenesis 2013 ;2( ):e60

Mouse models of the skin: models to define mechanisms of skin carcinogenesisWheeler,D. L.; Verma,A. K.; Denning,M. F.Journal of skin cancer 2013 ;2013( ):971495

Long QT2 mutation on the Kv11.1 ion channel inhibits current activity by ablating a protein kinase Calpha consensus siteDonovan,A. J.; Lansu,K.; Williams,J. G.; Denning,M. F.; Gentile,S.Molecular pharmacology 2012 ;82(3):428-437

Specifying protein kinase C functions in melanomaDenning,M. F.Pigment Cell & Melanoma Research 2012 ;25(4):466-476

The black box illuminated: signals and signalingMascia,F.; Denning,M.; Kopan,R.; Yuspa,S. H.The Journal of investigative dermatology 2012 ;132(3 Pt 2):811-819

The calcium ATPase SERCA2 regulates desmoplakin dynamics and intercellular adhesive strength through modulation of PKCα signalingHobbs,R. P.; Amargo,E. V.; Somasundaram,A.; Simpson,C. L.; Prakriya,M.; Denning,M. F.; Green,K. J.The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2011 ;25(3):990-1001

Fyn is induced by Ras/PI3K/Akt signaling and is required for enhanced invasion/migration.Yadav,V.; Denning,M. F.Molecular carcinogenesis 2011 ;50(5):346-352

Functional alterations in protein kinase C beta II expression in melanoma.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.Pigment Cell & Melanoma Research 2010 ;23(2):216-224

The protein kinase Cdelta catalytic fragment is critical for maintenance of the G2/M DNA damage checkpoint.LaGory,E. L.; Sitailo,L. A.; Denning,M. F.Journal of Biological Chemistry 2010 ;285(3):1879-1887

Loss of protein kinase C delta gene expression in human squamous cell carcinomas: a laser capture microdissection study.Yadav,V.; Yanez,N. C.; Fenton,S. E.; Denning,M. F.American Journal of Pathology 2010 ;176(3):1091-1096

Protein kinase C/mitogen-activated protein kinase signaling in keratinocyte differentiation control.Denning,M. F.Journal of Investigative Dermatology 2010 ;130(8):1968-1970

Sun-sensitizing effects of PKCepsilon shine on multiple mouse strains.Denning,M. F.Journal of Investigative Dermatology 2010 ;130(1):17-19

PDGF receptor activation induces p120-catenin phosphorylation at serine 879 via a PKCalpha-dependent pathwayBrown,M. V.; Burnett,P. E.; Denning,M. F.; Reynolds,A. B.Experimental cell research 2009 ;315(1):39-49

Role for protein kinase C-alpha in keratinocyte growth arrestJerome-Morais,A.; Rahn,H. R.; Tibudan,S. S.; Denning,M. F.Journal of Investigative Dermatology 2009 ;129(10):2365-2375

Mcl-1 functions as major epidermal survival protein required for proper keratinocyte differentiation.Sitailo,L. A.; Jerome-Morais,A.; Denning,M. F.Journal of Investigative Dermatology 2009 ;129(6):1351-1360

Inhibition of PAX3 by TGF-beta modulates melanocyte viability.Yang,G.; Li,Y.; Nishimura,E. K.; Xin,H.; Zhou,A.; Guo,Y.; Dong,L.; Denning,M. F.; Nickoloff,B. J.; Cui,R.Molecular cell 2008 ;32(4):554-563

Plakophilin 2: a critical scaffold for PKC alpha that regulates intercellular junction assembly.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.Journal of Cell Biology 2008 ;181(4):605-613

Tightening the epidermal barrier with atypical PKCsDenning,M. F.Journal of Investigative Dermatology 2007 ;127(4):742-744

Protein kinase C family: on the crossroads of cell signaling in skin and tumor epitheliumBreitkreutz,D.; Braiman-Wiksman,L.; Daum,N.; Denning,M. F.; Tennenbaum,T.Journal of Cancer Research & Clinical Oncology 2007 ;133(11):793-808

The protein kinase C delta catalytic fragment targets Mcl-1 for degradation to trigger apoptosis.Sitailo,L. A.; Tibudan,S. S.; Denning,M. F.Journal of Biological Chemistry 2006 ;281(40):29703-29710

Enhanced killing of melanoma cells by simultaneously targeting Mcl-1 and NOXA.Qin,J. Z.; Xin,H.; Sitailo,L. A.; Denning,M. F.; Nickoloff,B. J.Cancer research 2006 ;66(19):9636-9645

PKCdelta clustering at the leading edge and mediating growth factor-enhanced, but not ecm-initiated, dermal fibroblast migration.Fan,J.; Guan,S.; Cheng,C. F.; Cho,M.; Fields,J. W.; Chen,M.; Denning,M. F.; Woodley,D. T.; Li,W.Journal of Investigative Dermatology 2006 ;126(6):1233-1243

Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin.Guo,H.; Miao,H.; Gerber,L.; Singh,J.; Denning,M. F.; Gilliam,A. C.; Wang,B.Cancer research 2006 ;66(14):7050-7058

The proapoptotic tumor suppressor protein kinase C-delta is lost in human squamous cell carcinomas.D'Costa,A. M.; Robinson,J. K.; Maududi,T.; Chaturvedi,V.; Nickoloff,B. J.; Denning,M. F.Oncogene 2006 ;25(3):378-386

Defining the caspase-containing apoptotic machinery contributing to cornification in human epidermal equivalents.Chaturvedi,V.; Sitailo,L. A.; Bodner,B.; Denning,M. F.; Nickoloff,B. J.Experimental dermatology 2006 ;15(1):14-22

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-x(L) reduction thereby enhancing UV-light induced apoptosis.Chaturvedi,V.; Sitailo,L. A.; Qin,J. Z.; Bodner,B.; Denning,M. F.; Curry,J.; Zhang,W.; Brash,D.; Nickoloff,B. J.Oncogene 2005 ;24(34):5299-5312

A caspase-resistant mutant of PKC-delta protects keratinocytes from UV-induced apoptosis.D'Costa,A. M.; Denning,M. F.Cell Death & Differentiation 2005 ;12(3):224-232

Survival role of protein kinase C (PKC) in chronic lymphocytic leukemia and determination of isoform expression pattern and genes altered by PKC inhibition.Alkan,S.; Huang,Q.; Ergin,M.; Denning,M. F.; Nand,S.; Maududi,T.; Paner,G. P.; Ozpuyan,F.; Izban,K. F.American Journal of Hematology 2005 ;79(2):97-106

Bax activation and induction of apoptosis in human keratinocytes by the protein kinase C delta catalytic domain.Sitailo,L. A.; Tibudan,S. S.; Denning,M. F.Journal of Investigative Dermatology 2004 ;123(3):434-443

Low-dose UV-radiation sensitizes keratinocytes to TRAIL-induced apoptosis.Qin,J. Z.; Bacon,P.; Panella,J.; Sitailo,L. A.; Denning,M. F.; Nickoloff,B. J.Journal of cellular physiology 2004 ;200(1):155-166

Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoformsDenning,M. F.International Journal of Biochemistry & Cell Biology 2004 ;36(7):1141-1146

Role for Id-1 in immunobiology of normal keratinocytes and in basal cell carcinoma.Chaturvedi,V.; Bonish,B.; Bacon,P.; Qin,J. Z.; Denning,M. F.; Foreman,K. E.; Diaz,M. O.; Robinson,J.; Nickoloff,B. J.Experimental dermatology 2003 ;12(3):255-260

Protein kinase C-delta is commonly expressed in multiple myeloma cells and its downregulation by rottlerin causes apoptosis.Ni,H.; Ergin,M.; Tibudan,S. S.; Denning,M. F.; Izban,K. F.; Alkan,S.British journal of haematology 2003 ;121(6):849-856

Life and death signaling pathways contributing to skin cancerNickoloff,B. J.; Qin,J. Z.; Chaturvedi,V.; Bacon,P.; Panella,J.; Denning,M. F.The journal of investigative dermatology.Symposium proceedings / the Society for Investigative Dermatology, Inc.[and] European Society for Dermatological Research 2002 ;7(1):27-35

Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgammaNickoloff,B. J.; Qin,J. Z.; Chaturvedi,V.; Denning,M. F.; Bonish,B.; Miele,L.Cell death and differentiation 2002 ;9(8):842-855

Activation of protein kinase C triggers irreversible cell cycle withdrawal in human keratinocytesTibudan,S. S.; Wang,Y.; Denning,M. F.The Journal of investigative dermatology 2002 ;119(6):1282-1289

P21Waf1 control of epithelial cell cycle and cell fateWeinberg,W. C.; Denning,M. F.Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists 2002 ;13(6):453-464

Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytesQin,J. Z.; Chaturvedi,V.; Denning,M. F.; Bacon,P.; Panella,J.; Choubey,D.; Nickoloff,B. J.Oncogene 2002 ;21(19):2991-3002

Activation of caspase-9 is required for UV-induced apoptosis of human keratinocytesSitailo,L. A.; Tibudan,S. S.; Denning,M. F.The Journal of biological chemistry 2002 ;277(22):19346-19352

Caspase activation and disruption of mitochondrial membrane potential during UV radiation-induced apoptosis of human keratinocytes requires activation of protein kinase CDenning,M. F.; Wang,Y.; Tibudan,S.; Alkan,S.; Nickoloff,B. J.; Qin,J. Z.Cell death and differentiation 2002 ;9(1):40-52

Inhibition of tyrosine kinase activity induces caspase-dependent apoptosis in anaplastic large cell lymphoma with NPM-ALK (p80) fusion proteinErgin,M.; Denning,M. F.; Izban,K. F.; Amin,H. M.; Martinez,R. L.; Saeed,S.; Alkan,S.Experimental hematology 2001 ;29(9):1082-1090

Phosphorylation of murine homeodomain protein Dlx3 by protein kinase CPark,G. T.; Denning,M. F.; Morasso,M. I.FEBS letters 2001 ;496(1):60-65

Abnormal NF-kappaB signaling pathway with enhanced susceptibility to apoptosis in immortalized keratinocytesChaturvedi,V.; Qin,J. Z.; Denning,M. F.; Choubey,D.; Diaz,M. O.; Nickoloff,B. J.Journal of dermatological science 2001 ;26(1):67-78

Protein kinase Cdelta-mediated phosphorylation of alpha6beta4 is associated with reduced integrin localization to the hemidesmosome and decreased keratinocyte attachmentAlt,A.; Ohba,M.; Li,L.; Gartsbein,M.; Belanger,A.; Denning,M. F.; Kuroki,T.; Yuspa,S. H.; Tennenbaum,T.Cancer research 2001 ;61(11):4591-4598

Characterization of apoptosis induced by protein kinase C inhibitors and its modulation by the caspase pathway in acute promyelocytic leukaemiaAmin,H. M.; Ergin,M.; Denning,M. F.; Quevedo,M. E.; Alkan,S.British journal of haematology 2000 ;110(3):552-562

Id-1 delays senescence but does not immortalize keratinocytesNickoloff,B. J.; Chaturvedi,V.; Bacon,P.; Qin,J. Z.; Denning,M. F.; Diaz,M. O.The Journal of biological chemistry 2000 ;275(36):27501-27504

Cross-talk between epidermal growth factor receptor and protein kinase C during calcium-induced differentiation of keratinocytesDenning,M. F.; Dlugosz,A. A.; Cheng,C.; Dempsey,P. J.; Coffey,R. J.,Jr; Threadgill,D. W.; Magnuson,T.; Yuspa,S. H.Experimental dermatology 2000 ;9(3):192-199

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