Signal-specific co-activator domain requirements for Pit-1 activation

Abstract

POU-domain proteins, such as the pituitary-specific factor Pit-1, are members of the homeodomain family of proteins which are important in development and homeostasis, acting constitutively or in response to signal-transduction pathways to either repress or activate the expression of specific genes1. Here we show that whereas homeodomain-containing repressors such as Rpx2 seem to recruit only a co-repressor complex, the activity of Pit-1 (ref. 3) is determined by a regulated balance between a co-repressor complex that contains N-CoR/SMRT4,5, mSin3A/B6,7,8 and histone deacetylases6,7,8 and a co-activator complex that includes the CREB-binding protein (CBP)9 and p/CAF10. Activation of Pit-1 by cyclic AMP or growth factors depends on distinct amino- and carboxy-terminal domains of CBP, respectively. Furthermore, thehistone acetyltransferase functions of CBP11,12 or p/CAF10 are required for Pit-1 function that is stimulated by cyclic AMP or growth factors, respectively. These data show that there is a switch in specific requirements for histone acetyltransferases and CBP domains in mediating the effects of different signal-transduction pathways on specific DNA-bound transcription factors.

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Figure 1: Role of N-CoR repression in Pit-1 function.
Figure 2: Requirement for N-CoR co-repressor complex in the repression function of Rpx.
Figure 3: CBP is a required co-activator of Pit-1.
Figure 4: Activation of Pit-1 function by signal-transduction pathways is mediated through the CBP complex.
Figure 5: Requirements of HAT functions and domains of CBP for growth-factor-stimulated Pit-1 function.

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Acknowledgements

We thank C. Laherty, R. Eisenman, W.-M. Yang and E. Seto for antibodies, C. Nelson for cell culture, L.-M. Philips for assistance, and P. Meyer for her expertise in the preparation of the illustrations. This work was supported by an American Heart Association Predoctoral fellowship (L.X.), the NSF (R.M.L.), the Lucille Markey Fund (J.S.D.), and an NIH predoctoral fellowship (D.S.), a US Army Medical Research Program Award (E.K.), by grants from HHMI and NIH (to M.G.R.), and by an American Diabetes Association Career Development Award (to D.W.R.). C.K.G. is an Established Investigator of the American Heart Association and M.G.R. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Michael G. Rosenfeld.

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