Identification of a mouse thiamine transporter gene as a direct transcriptional target for p53.
p53 tumor suppressor is a transcription factor that functions, in part, through many of its downstream target genes. We have identified a p53-inducible gene by performing mRNA differential display on IW32 murine erythroleukemia cells containing a temperature-sensitive p53 mutant allele, tsp53(Val-135). Sequence analysis of the full-length cDNA revealed its identity as the mouse homologue of the human thiamine transporter 1 (THTR-1). Induction of the mouse THTR-1 (mTHTR-1) mRNA was detectable as early as 1 h at 32.5 degrees C; upon shifting back to 38.5 degrees C, mTHTR-1 transcript was rapidly degraded with a half-life of less than 2 h. Elevation of mTHTR-1 expression was found in DNA damage-induced normal mouse embryonic fibroblast cells, but not in p53(-/-) mouse embryonic fibroblast cells, suggesting that mTHTR-1 induction was p53-dependent. A region within the first intron of the mTHTR-1 gene bound to p53 and conferred the p53-mediated transactivation. Furthermore, increased thiamine transporter activities were found in cells overexpressing mTHTR-1 and under conditions of DNA damage or p53 activation. Our findings indicate that p53 may be involved in maintaining thiamine homeostasis through transactivation of THTR-1.
Lo
P K
PK
Institute of Biochemistry, National Yang Ming University, Shih-Pai, Taipei 112, Taiwan.
Chen
J Y
JY
Tang
P P
PP
Lin
J
J
Lin
C H
CH
Su
L T
LT
Wu
C H
CH
Chen
T L
TL
Yang
Y
Y
Wang
F F
FF
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000032:analysis; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013831:Thiamine / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D018076:DNA, Complementary; D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; C492292:Slc19a2 protein, mouse; D016159:Tumor Suppressor Protein p53; D013831:Thiamine