Rb Enhances p160/SRC Coactivator-dependent Activity of Nuclear Receptors and Hormone Responsiveness

Éric Batsché,Julien Desroches,Steve Bilodeau,Yves Gauthier,Jacques Drouin

doi:10.1074/jbc.m413428200

Éric Batsché, Julien Desroches + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m413428200

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Abstract

The retinoblastoma tumor suppressor protein (Rb) is best known as a repressor of genes involved in cell cycle progression. Rb has also been implicated in activation of transcription, in particular by nuclear receptors (NRs) and by differentiation-related transcription factors, but the relevance of this activity is unclear. We show that Rb and the related proteins p107 and p130 enhance the activity of NRs related to NGFI-B (Nur factors) through direct interactions with NGFI-B and SRC-2. Although recruitment of SRC/p160 coactivators to the NGFI-B AF1 domain is independent of Rb, its presence enhances SRC-dependent transcription. Rb potentiation of SRC coactivators is exerted on a subset (Nur factors, hepatocyte nuclear factor-4 (HNF-4), SF-1, and ER) but not all NRs. The levels of Rb-related proteins modulate hormone responsiveness of the NGFI-B-dependent pituitary proopiomelanocortin gene and HNF-4-dependent transcription during enterocyte differentiation. Increased Rb expression upon cell differentiation may promote differentiated functions, at least in part, by potentiation of NR activity.

Highlights

Mice mutant for one copy of the Rb1 gene always develop tumors of pituitary pro-opiomelanocortin (POMC)1-expressing cells [1], in contrast to humans where RB1 inactivation is associated with retinoblastoma and not directly with pituitary tumorigenesis
retinoblastoma tumor suppressor protein (Rb) Activates POMC Transcription through the Nur response element (NurRE)—To determine whether the POMC gene is a target of Rb regulation, we investigated the ability of Rb to modulate POMC promoter activity using transient co-transfection in POMC-expressing
Using a panel of POMC promoter mutants, we found two different response elements that are targeted by Rb: one is the NurRE and the other is the Eboxneuro that is the target of NeuroD1-containing basic helix-loop-helix dimers [25]

Summary

Introduction

Mice mutant for one copy of the Rb1 gene always develop tumors of pituitary pro-opiomelanocortin (POMC)1-expressing cells [1], in contrast to humans where RB1 inactivation is associated with retinoblastoma and not directly with pituitary tumorigenesis. Rb potentiation of SRC coactivators is exerted on a subset (Nur factors, hepatocyte nuclear factor-4 (HNF-4), SF-1, and ER) but not all NRs. The levels of Rb-related proteins modulate hormone responsiveness of the NGFI-B-dependent pituitary proopiomelanocortin gene and HNF-4-dependent transcription during enterocyte differentiation. NGFI-B stimulated NurRE-dependent transcription in both cells, and these activities were enhanced by SRC-2 (Fig. 2E).

Results

Conclusion