title: Kr-pok increases FASN expression by modulating the DNA binding of SREBP-1c and Sp1 at the proximal promoter.
abstract: Kr-pok (kidney cancer-related POZ domain and Krüppel-like protein) is a new proto-oncogenic POZ-domain transcription factor. Fatty acid synthase gene (FASN) encodes one of the key enzymes in fatty acids synthesis and is the only enzyme that synthesizes fatty acids in cancer cells. Sp1 and SREBP-1c are the two major transcription activators of FASN. We investigated whether Kr-pok modulates transcription of the FASN. FASN expression is significantly decreased in Kr-pok knockout murine embryonic fibroblasts. Coimmunoprecipitation, GST fusion protein pull-down, and immunocytochemistry assays show that the zinc-finger domain of Kr-pok interacts directly with the bZIP DNA binding domain of SREBP-1. Electrophoretic mobility shift assay, oligonucleotide pull-down, and chromatin immunoprecipitation assays showed that Kr-pok changes the transcription factor binding dynamics of Sp1 and SREBP-1c to the SRE/E-box elements of the proximal promoter. We found that Kr-pok expression increased during 3T3-L1 preadipocyte differentiation and that FASN expression is decreased by the knockdown of Kr-pok. Kr-pok facilitates the SREBP-1c-mediated preadipocyte differentiation and/or fatty acid synthesis. Kr-pok may act as an important regulator of fatty acid synthesis and may induce rapid cancer cell proliferation by increasing palmitate synthesis.
authors.affiliation: Department of Biochemistry, Brain Korea 21 Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 134, ShinChon-Dong, SeoDaeMoon-Ku, Seoul, 120-752, Korea.
authors.forename: Bu-Nam
authors.initials: BN
authors.lastname: Jeon
authors.forename: Yeon-Sook
authors.initials: YS
authors.lastname: Kim
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Choi
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Koh
authors.forename: Min-Kyeong
authors.initials: MK
authors.lastname: Kim
authors.forename: Jae-Hyeon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hur
authors.forename: Philip Dong-Hyun
authors.initials: PD
authors.lastname: Paik
authors.forename: Man-Wook
authors.initials: MW
authors.lastname: Hur
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D049109:Cell Proliferation; D004318:Doxycycline / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C110461:ZBTB7C protein, human; D054890:Fatty Acid Synthase, Type I; D004318:Doxycycline