Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1.
Recruitment of p300/CBP by the hypoxia-inducible factor, HIF-1, is essential for the transcriptional response to hypoxia and requires an interaction between the p300/CBP CH1 region and HIF-1alpha. A new p300-CH1 interacting protein, p35srj, has been identified and cloned. p35srj is an alternatively spliced isoform of MRG1, a human protein of unknown function. Virtually all endogenous p35srj is bound to p300/CBP in vivo, and it inhibits HIF-1 transactivation by blocking the HIF-1alpha/p300 CH1 interaction. p35srj did not affect transactivation by transcription factors that bind p300/CBP outside the CH1 region. Endogenous p35srj is up-regulated markedly by the HIF-1 activators hypoxia or deferoxamine, suggesting that it could operate in a negative-feedback loop. In keeping with this notion, a p300 CH1 mutant domain, defective in HIF-1 but not p35srj binding, enhanced endogenous HIF-1 function. In hypoxic cells, p35srj may regulate HIF-1 transactivation by controlling access of HIF-1alpha to p300/CBP, and may keep a significant portion of p300/CBP available for interaction with other transcription factors by partially sequestering and functionally compartmentalizing cellular p300/CBP.
Bhattacharya
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S
The Dana-Farber Cancer Institute and the Harvard Medical School, Boston, Massachusetts 02115, USA.
Michels
C L
CL
Leung
M K
MK
Arany
Z P
ZP
Kung
A L
AL
Livingston
D M
DM
D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*
C486381:CITED2 protein, human; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors