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Inhibition of histone acetyltransferase function of p300 by PKCdelta
L W Yuan1, Jae-Won Soh, I Bernard Weinstein
1Department of Physiology and Biophysics, School of Medicine, Boston University, 715 Albany St., MA 02118, USA. yuan1w01@yahoo.com
Abstract:
Protein kinase Cdelta (PKCdelta) is one of the functionally distinct isoforms in PKC family. p300 is a histone acetyltransferase/transcription coactivator. They share certain properties, such as ubiquitous expression, growth and tumor suppression, and ability to enhance differentiation and apoptosis. In this study, we found that PKCdelta but not classical PKC, specifically phosphorylates p300 at serine 89 in vitro and in vivo. This phosphorylation causes inhibition of p300 intrinsic HAT activity. Subsequently, the targeted acetylation of nucleosomal histones is markedly reduced, which causes repression of p300 transcription coactivator function. These findings identify a new signal transduction pathway by which PKCdelta may inhibit cell growth and promote cellular differentiation.
Insights
Protein kinase Cdelta (PKCdelta) phosphorylates p300, a key coactivator, inhibiting its HAT activity. This novel pathway suggests PKCdelta
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Signaling
Background:
- Protein kinase Cdelta (PKCdelta) is a distinct isoform within the PKC family.
- p300 functions as a histone acetyltransferase (HAT) and transcription coactivator.
- Both PKCdelta and p300 are implicated in growth suppression, differentiation, and apoptosis.
Purpose of the Study:
- To investigate the interaction and functional relationship between PKCdelta and p300.
- To identify specific phosphorylation sites on p300 by PKCdelta.
- To elucidate the impact of this phosphorylation on p300's HAT activity and coactivator function.
Main Methods:
- In vitro kinase assays to determine PKCdelta's specificity.
- In vivo studies to confirm phosphorylation in cellular contexts.
- Assays to measure histone acetyltransferase (HAT) activity.
- Analysis of nucleosomal histone acetylation levels.
Main Results:
- PKCdelta specifically phosphorylates p300 at serine 89, both in vitro and in vivo.
- This phosphorylation event inhibits the intrinsic HAT activity of p300.
- Reduced p300 HAT activity leads to decreased acetylation of nucleosomal histones.
- The transcription coactivator function of p300 is repressed.
Conclusions:
- PKCdelta directly regulates p300 activity through phosphorylation at serine 89.
- This novel signaling pathway mediated by PKCdelta inhibits p300's role in histone acetylation.
- The findings suggest a mechanism by which PKCdelta may suppress cell growth and promote differentiation.