PCAF

Structure

Several domains of PCAF can act independently or in unison to enable its functions. PCAF has separate acetyltransferase and E3 ubiquitin ligase domains as well as a bromodomain for interaction with other proteins. PCAF also possesses sites for its own acetylation and ubiquitination.

Function

CBP and p300 are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun and the adenoviral oncoprotein E1A. The protein encoded by the PCAF gene associates with p300/CBP. It has in vitro and in vivo binding activity with CBP and p300, and competes with E1A for binding sites in p300/CBP. It has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that this protein plays a direct role in transcriptional regulation.

Regulation

The acetyltransferase activity and cellular location of PCAF are regulated through acetylation of PCAF itself. PCAF may be autoacetylated (acetylated by itself) or by p300. Acetylation leads to migration to the nucleus and enhances its acetyltransferase activity. PCAF interacts with and is deacetylated by HDAC3, leading to a reduction in PCAF acetyltransferase activity and cytoplasmic localisation.

Protein interactions

PCAF forms complexes with numerous proteins that guide its activity. For example PCAF is recruited by ATF to acetylate histones and promote transcription of ATF4 target genes.

Targets

There are various protein targets of PCAF's acetyltransferase activity including transcription factors such as Fli1, p53 and numerous histone residues. Hdm2, itself a ubiquitin ligase that targets p53, has also been demonstrated to be a target of the ubiquitin-ligase activity of PCAF.

Interactions

PCAF has been shown to interact with:

• BRCA2,
• CTNNB1,
• CREBBP,
• EVI1,
• HNF1A,
• IRF1,
• IRF2,
• KLF13,
• Mdm2
• Myc,
• NCOA1,
• POLR2A,
• RBPJ,
• TCF3,
• TRRAP, and
• TWIST1.

References

References

1. (March 2007). "Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2". Nat. Cell Biol..
2. "Entrez Gene: PCAF p300/CBP-associated factor".
3. (August 2003). "Mechanisms of P/CAF auto-acetylation". Nucleic Acids Res..
4. (February 2007). "Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2". Mol. Cell. Biol..
5. (2007). "The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP". Nucleic Acids Res..
6. (November 2007). "Transforming growth factor-beta regulates DNA binding activity of transcription factor Fli1 by p300/CREB-binding protein-associated factor-dependent acetylation". J. Biol. Chem..
7. (February 1999). "p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage". Mol. Cell. Biol..
8. (Sep 2003). "M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex". J. Biol. Chem..
9. (Nov 1998). "BRCA2 associates with acetyltransferase activity when bound to P/CAF". Oncogene.
10. (Jan 2009). "PCAF acetylates {beta}-catenin and improves its stability". Mol. Biol. Cell.
11. (Feb 2002). "Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription". Mol. Cell.
12. (Sep 1998). "A human RNA polymerase II complex containing factors that modify chromatin structure". Mol. Cell. Biol..
13. (Nov 2001). "Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles". J. Biol. Chem..
14. (Apr 2000). "Transcriptional activation by hepatocyte nuclear factor-1 requires synergism between multiple coactivator proteins". J. Biol. Chem..
15. (Mar 1999). "The histone acetylase PCAF is a phorbol-ester-inducible coactivator of the IRF family that confers enhanced interferon responsiveness". Mol. Cell. Biol..
16. (Jun 2001). "Coactivator p300 acetylates the interferon regulatory factor-2 in U937 cells following phorbol ester treatment". J. Biol. Chem..
17. (Mar 2002). "Functional interaction between coactivators CBP/p300, PCAF, and transcription factor FKLF2". J. Biol. Chem..
18. (Aug 2002). "MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)-mediated p53 acetylation". J. Biol. Chem..
19. (May 2003). "c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation". J. Biol. Chem..
20. (Sep 1997). "Steroid receptor coactivator-1 is a histone acetyltransferase". Nature.
21. (Jun 2000). "Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5". J. Biol. Chem..
22. (Jan 2003). "Regulation of E2A activities by histone acetyltransferases in B lymphocyte development". J. Biol. Chem..
23. (Aug 2001). "The p400 complex is an essential E1A transformation target". Cell.
24. (Feb 1999). "Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A". Cell.