title: A bifunctional intronic element regulates the expression of the arginine/lysine transporter Cat-1 via mechanisms involving the purine-rich element binding protein A (Pur alpha).
abstract: Expression of the arginine/lysine transporter Cat-1 is highly induced in proliferating and stressed cells via mechanisms that include transcriptional activation. A bifunctional INE (intronic element) within the first intron of the Cat-1 gene was identified and characterized in this study. The INE had high sequence homology to an amino acid response element and was shown to act as a transcriptional enhancer in unstressed cells by binding the transcription factor, purine-rich element binding protein A (Pur alpha). During endoplasmic reticulum stress, binding of Pur alpha to the INE decreased; the element acted as a positive regulator in early stress by binding of the transcription factor ATF4 and as a negative regulator in prolonged stress by binding the stress-induced C/EBP family member, CHOP. We conclude that transcriptional control of the Cat-1 gene is tightly controlled by multiple cis-DNA elements, contributing to regulation of cationic amino acid transport for cell growth and proliferation. In addition, we propose that genes may use stress-response elements such as the INE to support basal expression in the absence of stress.
authors.affiliation: Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4954, USA.
authors.forename: Charlie C
authors.initials: CC
authors.lastname: Huang
authors.forename: Calin-Bogdan
authors.initials: CB
authors.lastname: Chiribau
authors.forename: Mithu
authors.initials: M
authors.lastname: Majumder
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kelm
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
authors.forename: Martin D
authors.initials: MD
authors.lastname: Snider
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051381:Rats; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C497109:ATF4 protein, human; D027201:Cationic Amino Acid Transporter 1; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C501130:PURA protein, human; C508559:PurA protein, rat; C121485:Pura protein, mouse; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D004247:DNA