title: Differential regulation of cyclin D1 expression by protein kinase C α and ϵ signaling in intestinal epithelial cells.
abstract: Cellular accumulation of cyclin D1, a key regulator of cell proliferation and tumorigenesis, is subject to tight control. Our previous studies have identified PKCα as a negative regulator of cyclin D1 in the intestinal epithelium. However, treatment of non-transformed IEC-18 ileal crypt cells with PKC agonists has a biphasic effect on cyclin D1 expression. Initial PKCα-mediated down-regulation is followed by recovery and subsequent accumulation of the cyclin to levels markedly higher than those seen in untreated cells. Using protein overexpression strategies, siRNA, and pharmacological inhibitors, we now demonstrate that the recovery and hyperinduction of cyclin D1 reflect the combined effects of (a) loss of negative signals from PKCα due to agonist-induced PKCα down-regulation and (b) positive effects of PKCϵ. PKCϵ-mediated up-regulation of cyclin D1 requires sustained ERK stimulation and transcriptional activation of the proximal cyclin D1 (CCDN1) promoter, without apparent involvement of changes in protein stability or translation. PKCϵ also up-regulates cyclin D1 expression in colon cancer cells, through mechanisms that parallel those in IEC-18 cells. Although induction of cyclin D1 by PKCϵ is dependent on non-canonical NF-κB activation, the NF-κB site in the proximal promoter is not required. Instead, cyclin D1 promoter activity is regulated by a novel interaction between NF-κB and factors that associate with the cyclic AMP-response element adjacent to the NF-κB site. The differential effects of PKCα and PKCϵ on cyclin D1 accumulation are likely to contribute to the opposing tumor-suppressive and tumor-promoting activities of these PKC family members in the intestinal epithelium.
authors.affiliation: the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Marybeth A
authors.initials: MA
authors.lastname: Pysz
authors.affiliation: the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Fang
authors.initials: F
authors.lastname: Hao
authors.affiliation: the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: A Asli
authors.initials: AA
authors.lastname: Hizli
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198 and.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lum
authors.affiliation: the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Swetzig
authors.affiliation: the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263From the Eppley Institute for Research in Cancer and Allied Diseases and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198 and.
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Black
authors.affiliation: the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263From the Eppley Institute for Research in Cancer and Allied Diseases and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198 and.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Black
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D019940:Genes, bcl-1; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: C530104:CCND1 protein, human; C530106:Ccnd1 protein, rat; D016328:NF-kappa B; D012333:RNA, Messenger; D019938:Cyclin D1; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon
keywords: Colon Cancer; Cyclic AMP-response Element (CRE); Cyclin D1; Extracellular Signal-regulated Kinase (ERK); Intestine; NF-kappaB; PKCalpha; PKCepsilon; Protein Kinase C (PKC)