FUNCTIONAL INTERFERENCE BETWEEN THE UBIQUITOUS AND CONSTITUTIVE OCTAMER TRANSCRIPTION FACTOR-I (OTF-1) AND THE GLUCOCORTICOID RECEPTOR BY DIRECT PROTEIN-PROTEIN INTERACTION INVOLVING THE HOMEO SUBDOMAIN OF OTF-1

被引:95
作者
KUTOH, E [1 ]
STROMSTEDT, PE [1 ]
POELLINGER, L [1 ]
机构
[1] HUDDINGE UNIV HOSP, KAROLINSKA INST, DEPT MED NUTR, F60, S-14186 HUDDINGE, SWEDEN
关键词
D O I
10.1128/MCB.12.11.4960
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The ubiquitous and constitutive octamer transcription factor OTF-1 (Oct 1) is the target of positive regulation by the potent herpes simplex virus trans-activator VP16, which forms a complex with the homeodomain of OTF-1. Here we present evidence that the glucocorticoid receptor can negatively regulate OTF-1 function by a mechanism that is independent of DNA binding. In vivo-expressed glucocorticoid receptor inhibited in a hormone-dependent manner activation of a minimal promoter construct carrying a functional octamer site. Moreover, expression of the receptor in vivo resulted in hormone-dependent repression of OTF-1-dependent DNA-binding activity in nuclear extract. In vitro, the DNA-binding activity of partially purified OTF-1 was repressed following incubation with purified glucocorticoid receptor. Cross-linking and immunoprecipitation experiments indicated that the functional interference may be due to a strong association between these two proteins in solution. Finally, preliminary evidence indicates that the homeo subdomain of OTF-1 that directs formation of a complex with VP16 may also be critical for interaction with the glucocorticoid receptor. Thus, OTF-1 is a target for both positive and negative regulation by protein-protein interaction. Moreover, the functional interference between OTF-1 and the glucocorticoid receptor represents a novel regulatory mechanism in the cross-coupling of signal transduction pathways of nuclear receptors and constitutive transcription factors.
引用
收藏
页码:4960 / 4969
页数:10
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