title: Opposing growth regulatory roles of protein kinase D isoforms in human keratinocytes.
abstract: PKD is a family of three serine/threonine kinases (PKD-1, -2, and -3) involved in the regulation of diverse biological processes including proliferation, migration, secretion, and cell survival. We have previously shown that despite expression of all three isoforms in mouse epidermis, PKD1 plays a unique and critical role in wound healing, phorbol ester-induced hyperplasia, and tumor development. In translating our findings to the human, we discovered that PKD1 is not expressed in human keratinocytes (KCs) and there is a divergence in the expression and function of other PKD isoforms. Contrary to mouse KCs, treatment of cultured human KCs with pharmacological inhibitors of PKDs resulted in growth arrest. We found that PKD2 and PKD3 are expressed differentially in proliferating and differentiating human KCs, with the former uniformly present in both compartments whereas the latter is predominantly expressed in the proliferating compartment. Knockdown of individual PKD isoforms in human KCs revealed contrasting growth regulatory roles for PKD2 and PKD3. Loss of PKD2 enhanced KC proliferative potential while loss of PKD3 resulted in a progressive proliferation defect, loss of clonogenicity and diminished tissue regenerative ability. This proliferation defect was correlated with up-regulation of CDK4/6 inhibitor p15(INK4B) and induction of a p53-independent G1 cell cycle arrest. Simultaneous silencing of PKD isoforms resulted in a more pronounced proliferation defect consistent with a predominant role for PKD3 in proliferating KCs. These data underline the importance and complexity of PKD signaling in human epidermis and suggest a central role for PKD3 signaling in maintaining human epidermal homeostasis.
authors: From the Graduate Program in Molecular and Cell Biology and.
authors: Vladislav
authors: V
authors: Ryvkin
authors: Department of Oral Biology and Pathology, Stony Brook University, Stony Brook, New York 11794.
authors: Mohammad
authors: M
authors: Rashel
authors: Department of Oral Biology and Pathology, Stony Brook University, Stony Brook, New York 11794.
authors: Trivikram
authors: T
authors: Gaddapara
authors: From the Graduate Program in Molecular and Cell Biology and Department of Oral Biology and Pathology, Stony Brook University, Stony Brook, New York 11794 soosan.ghazizadeh@stonybrook.edu.
authors: Soosan
authors: S
authors: Ghazizadeh
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis / Q000235:genetics; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D007527:Isoenzymes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C089212:protein kinase D; D011493:Protein Kinase C
keywords: cell cycle; cell proliferation; differentiation; epidermis; keratinocytes; protein kinase D (PKD)