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Histone acetyltransferase activity of CBP is controlled by cycle-dependent kinases and oncoprotein E1A
S Ait-Si-Ali1, S Ramirez, F X Barre
1Laboratoire Oncogénèse, Différenciation et Transduction du Signal, CNRS UPR 9079, Villejuif, France.
Abstract:
Transforming viral proteins such as E1A force cells through the restriction point of the cell cycle into S phase by forming complexes with two cellular proteins: the retinoblastoma protein (Rb), a transcriptional co-repressor, and CBP/p300, a transcriptional co-activator. These two proteins locally influence chromatin structure: Rb recruits a histone deacetylase, whereas CBP is a histone acetyltransferase. Progression through the restriction point is triggered by phosphorylation of Rb, leading to disruption of Rb-associated repressive complexes and allowing the activation of S-phase genes. Here we show that CBP, like Rb, is controlled by phosphorylation at the G1/S boundary, increasing its histone acetyltransferase activity. This enzymatic activation is mimicked by E1A.
Insights
Viral protein E1A hijacks cell cycle progression by binding retinoblastoma protein (Rb) and CBP/p300. Phosphorylation of CBP/p300 enhances its activity, mimicking E1A
Area of Science:
- Cell biology
- Molecular biology
- Virology
Background:
- Viral oncoproteins like E1A manipulate the host cell cycle.
- Retinoblastoma protein (Rb) and CBP/p300 are key regulators of the G1/S cell cycle transition.
- Rb acts as a co-repressor, recruiting histone deacetylases, while CBP/p300 acts as a co-activator, possessing histone acetyltransferase activity.
Purpose of the Study:
- To investigate the regulation of CBP/p300 activity during the cell cycle.
- To determine if CBP/p300 is subject to phosphorylation at the G1/S boundary.
- To compare the effects of viral protein E1A on CBP/p300 activity with endogenous regulatory mechanisms.
Main Methods:
- Cell cycle analysis
- Protein immunoprecipitation
- Western blotting
- Enzyme activity assays
Main Results:
- CBP/p300 is phosphorylated at the G1/S boundary.
- Phosphorylation of CBP/p300 leads to increased histone acetyltransferase activity.
- Viral protein E1A mimics this phosphorylation-dependent activation of CBP/p300.
- E1A binding to Rb and CBP/p300 facilitates cell cycle progression into S phase.
Conclusions:
- CBP/p300 activity is regulated by phosphorylation at the G1/S transition.
- Viral protein E1A exploits this regulatory mechanism to drive cells into S phase.
- Understanding these interactions is crucial for comprehending viral oncogenesis and cell cycle control.