Staf50 is a novel p53 target gene conferring reduced clonogenic growth of leukemic U-937 cells.
The tumor suppressor gene p53 is a transcription factor that mediates both cell cycle arrest and apoptosis. Interestingly, p53 also induces differentiation of a number of tissues, including leukemic cells. However, although p53-mediated differentiation of leukemic U-937 cells depends on the transcriptional activity of p53, a p53 target gene mediating differentiation has hitherto not been identified. To screen for novel p53 target genes in leukemic cells, a cDNA microarray analysis was performed with U-937-4/ptsp53 cells, expressing a temperature-sensitive p53 mutant. We report that transcription of the Staf50 (stimulated transacting factor of 50 kDa) gene is upregulated in response to wild-type p53 in U-937-4, K562 and MCF-7 cells. Staf50 was directly activated by p53, as determined by the independence of de novo protein synthesis. Moreover, while the proximal promoter of Staf50 was found not to be p53 responsive, a functional enhancer-like p53-response element in intron 1 of the Staf50 gene was identified that was also transactivated by the p53-family member p73. Direct binding of p53 to the response element was shown by electrophoretic mobility shift analysis. Ectopic expression of Staf50 in U-937 cells resulted in reduced clonogenic growth. Moreover, levels of endogenous Staf50 mRNA correlated to all-trans retinoic acid-induced differentiation of promyelocytic NB-4 and HL60 cells, suggesting that Staf50 could be involved in proliferation and/or differentiation of leukemic cells.
Obad
Susanna
S
Department of Hematology, Lund University, BMC; C14, Lund S-221 84, Sweden.
Brunnström
Hans
H
Vallon-Christersson
Johan
J
Borg
Ake
A
Drott
Kristina
K
Gullberg
Urban
U
D020816:Amino Acid Motifs; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D022423:Myeloid Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D020298:U937 Cells
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C000606460:TP73 protein, human; C094314:TRIM22 protein, human; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014212:Tretinoin