title: p38δ regulates p53 to control p21Cip1 expression in human epidermal keratinocytes.
abstract: PKCδ suppresses keratinocyte proliferation via a mechanism that involves increased expression of p21(Cip1). However, the signaling mechanism that mediates this regulation is not well understood. Our present studies suggest that PKCδ activates p38δ leading to increased p21(Cip1) promoter activity and p21(Cip1) mRNA/protein expression. We further show that exogenously expressed p38δ increases p21(Cip1) mRNA and protein and that p38δ knockdown or expression of dominant-negative p38 attenuates this increase. Moreover, p53 is an intermediary in this regulation, as p38δ expression increases p53 mRNA, protein, and promoter activity, and p53 knockdown attenuates the activation. We demonstrate a direct interaction of p38δ with PKCδ and MEK3 and show that exogenous agents that suppress keratinocyte proliferation activate this pathway. We confirm the importance of this regulation using a stratified epidermal equivalent model, which mimics in vivo-like keratinocyte differentiation. In this model, PKCδ or p38δ knockdown results in reduced p53 and p21(Cip1) levels and enhanced cell proliferation. We propose that PKCδ activates a MEKK1/MEK3/p38δ MAPK cascade to increase p53 levels and p53 drives p21(Cip1) gene expression.
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Kamalika
authors.initials: K
authors.lastname: Saha
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Gautam
authors.initials: G
authors.lastname: Adhikary
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Santosh R
authors.initials: SR
authors.lastname: Kanade
authors.affiliation: Departments of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Rorke
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Obstetrics and Gynecology, and University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: reckert@umaryland.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D020405:Dermis / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D048292:Mitogen-Activated Protein Kinase 13; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human
keywords: Cell Differentiation; Cell Proliferation; Cell Signaling; MAP Kinases (MAPKs); p38 MAPK