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Gene Review

KAT2B  -  K(lysine) acetyltransferase 2B

Homo sapiens

Synonyms: CAF, GCN5, GCN5L, Histone acetylase PCAF, Histone acetyltransferase KAT2B, ...
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Disease relevance of PCAF

  • Structural basis of lysine-acetylated HIV-1 Tat recognition by PCAF bromodomain [1].
  • We report that the transcriptional co-activator PCAF and Tat interact and synergize to activate the HIV promoter [2].
  • Adenovirus E1B 55-kilodalton oncoprotein inhibits p53 acetylation by PCAF [3].
  • Using microarrays, we discovered that PCAF itself is induced by p53 in a panel of breast tumor cell lines [4].
  • We conclude that a non-classical transcriptional mechanism combats an anticellular action of poliovirus, through a TBP-free TAF-containing complex and GCN5 [5].

High impact information on PCAF


Chemical compound and disease context of PCAF


Biological context of PCAF

  • PCAF histone acetylase plays a role in regulation of transcription, cell cycle progression, and differentiation [10].
  • Acetylation at Lys50 creates a new site for binding to PCAF and dictates the formation of a ternary complex of Tat-PCAF-P-TEFb [15].
  • In transfection assays, PCAF represses cyclin B2, and a nonacetylated p53 mutant shows a complete loss of repression potential, despite its abilities to bind NF-Y and to be recruited on G(2)/M promoters [16].
  • p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage [17].
  • Using fluorescence resonance energy transfer analysis, we demonstrated that the acetylase PCAF and histone deacetylase 1 (HDAC1) are in close spatial proximity in living cells, compatible with their physical interaction [18].

Anatomical context of PCAF

  • Further studies showed that expression of PCAF and other histone acetylases was markedly induced in U937 cells upon phorbol ester treatment, which led to increased recruitment of PCAF to the IRF-ISRE complexes [19].
  • Conversely, PCAF levels were higher in MDM2-deficient mouse p53(-/-)/mdm2(-/-) embryonic fibroblast (MEF) cells than that in MDM2-containing MEF cells [20].
  • This stabilization is PCAF-dependent, since enforced expression in fetal/erythroid cells of a mutant form of PCAF lacking the histone acetyltransferase domain (PCAFDeltaHAT) decreases NF-E4 stability [21].
  • Consistently, overexpression of MDM2 in p53 null cells caused the reduction of the protein level of PCAF, but not the mRNA level [20].
  • In agreement, coimmunoprecipitation assays demonstrated that endogenous HDACs are associated with PCAF and another acetylase, GCN5, in HeLa cells [18].

Associations of PCAF with chemical compounds

  • Acetylation of CDP/cut by PCAF is directed at conserved lysine residues near the homeodomain region and regulates CDP/cut function [22].
  • The shuttling behavior and activity of the protein are regulated by acetylation: overexpression of PCAF or inhibition of cellular deacetylases by trichostatin A increases the nuclear accumulation of CIITA in a manner determined by the presence of the acetylation target lysines [23].
  • Restriction of PCAF in the nucleus by leptomycin B did not affect MDM2-mediated PCAF degradation [20].
  • A mutant human PCAF HAT domain (PCAF(Wloop)) was created in which the natural tryptophan (Trp-514) remote from the alpha5-beta6 loop was replaced with tyrosine and a glutamate within the loop (Glu-641) was substituted with tryptophan [24].
  • Utilizing a novel microplate fluorescent HAT assay which detects the enzymatic production of coenzyme A (CoA), we have compared the activities of the HAT domains of human PCAF and its GCN5 homologue from yeast and Tetrahymena and found that they have similar kinetic parameters [25].

Physical interactions of PCAF

  • MDM2 interacted with PCAF both in vitro and in cells, as assessed using GST fusion protein interaction and immunoprecipitation assays, respectively [26].
  • Interestingly, full-length IRF-2 in TPA-treated U937 cells occurred as a complex with p300 as well as PCAF and was itself acetylated [27].
  • However, a mutant that cannot be acetylated by PCAF due to a change in the surrounding amino acid context of lysine 92 showed increased DNA binding and activity compared with wild type IRF7 [28].
  • Furthermore, overexpression of PCAF results in an increase in the acetylation of histone H4 bound to the enhancer A and HDAC1 counteracts the PCAF-mediated H4 acetylation [29].
  • The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily [30].

Enzymatic interactions of PCAF


Regulatory relationships of PCAF


Other interactions of PCAF

  • Here we report cloning and characterization of the 400 kDa PCAF-associated factor referred to as PAF400 [30].
  • While hsGCN5 was predicted to be close to the size of the yeast acetyltransferase, hsP/CAF contained an additional 356 amino-terminal residues of unknown function [34].
  • The histone acetylases p300 and P/CAF directly acetylate the AR in vitro at a conserved KLKK motif [35].
  • Furthermore, MDM2 reduced the half-life of PCAF by 50% [20].
  • Consistent with these results, recombinant IRF-2 was acetylated by p300 and to a lesser degree by PCAF in vitro [27].

Analytical, diagnostic and therapeutic context of PCAF


  1. Structural basis of lysine-acetylated HIV-1 Tat recognition by PCAF bromodomain. Mujtaba, S., He, Y., Zeng, L., Farooq, A., Carlson, J.E., Ott, M., Verdin, E., Zhou, M.M. Mol. Cell (2002) [Pubmed]
  2. Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. Dorr, A., Kiermer, V., Pedal, A., Rackwitz, H.R., Henklein, P., Schubert, U., Zhou, M.M., Verdin, E., Ott, M. EMBO J. (2002) [Pubmed]
  3. Adenovirus E1B 55-kilodalton oncoprotein inhibits p53 acetylation by PCAF. Liu, Y., Colosimo, A.L., Yang, X.J., Liao, D. Mol. Cell. Biol. (2000) [Pubmed]
  4. The acetyltransferase p300/CBP-associated factor is a p53 target gene in breast tumor cells. Watts, G.S., Oshiro, M.M., Junk, D.J., Wozniak, R.J., Watterson, S., Domann, F.E., Futscher, B.W. Neoplasia (2004) [Pubmed]
  5. IFN-Stimulated transcription through a TBP-free acetyltransferase complex escapes viral shutoff. Paulson, M., Press, C., Smith, E., Tanese, N., Levy, D.E. Nat. Cell Biol. (2002) [Pubmed]
  6. E4F1 Is an Atypical Ubiquitin Ligase that Modulates p53 Effector Functions Independently of Degradation. Le Cam, L., Linares, L.K., Paul, C., Julien, E., Lacroix, M., Hatchi, E., Triboulet, R., Bossis, G., Shmueli, A., Rodriguez, M.S., Coux, O., Sardet, C. Cell (2006) [Pubmed]
  7. Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein. Seo, S.B., McNamara, P., Heo, S., Turner, A., Lane, W.S., Chakravarti, D. Cell (2001) [Pubmed]
  8. Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A. Hamamori, Y., Sartorelli, V., Ogryzko, V., Puri, P.L., Wu, H.Y., Wang, J.Y., Nakatani, Y., Kedes, L. Cell (1999) [Pubmed]
  9. A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity. Chakravarti, D., Ogryzko, V., Kao, H.Y., Nash, A., Chen, H., Nakatani, Y., Evans, R.M. Cell (1999) [Pubmed]
  10. Histone-like TAFs within the PCAF histone acetylase complex. Ogryzko, V.V., Kotani, T., Zhang, X., Schiltz, R.L., Howard, T., Yang, X.J., Howard, B.H., Qin, J., Nakatani, Y. Cell (1998) [Pubmed]
  11. Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. Perry, M.C., Kardinal, C.G., Korzun, A.H., Ginsberg, S.J., Raich, P.C., Holland, J.F., Ellison, R.R., Kopel, S., Schilling, A., Aisner, J. J. Clin. Oncol. (1987) [Pubmed]
  12. A randomized multicenter trial of cyclophosphamide, Novantrone and 5-fluorouracil (CNF) versus cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) in patients with metastatic breast cancer. Bennett, J.M., Byrne, P., Desai, A., White, C., DeConti, R., Vogel, C., Krementz, E., Muggia, F., Doroshow, J., Plotkin, D. Investigational new drugs. (1985) [Pubmed]
  13. Adjuvant chemohormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate for node-positive breast cancer patients. Hupperets, P.S., Wils, J., Volovics, L., Schouten, L., Fickers, M., Bron, H., Schouten, H.C., Jager, J., Smeets, J., de Jong, J. Ann. Oncol. (1993) [Pubmed]
  14. The Eastern Cooperative Oncology Group experience with cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer. Falkson, G., Gelman, R.S., Tormey, D.C., Cummings, F.J., Carbone, P.P., Falkson, H.C. Cancer (1985) [Pubmed]
  15. Differential acetylation of Tat coordinates its interaction with the co-activators cyclin T1 and PCAF. Brès, V., Tagami, H., Péloponèse, J.M., Loret, E., Jeang, K.T., Nakatani, Y., Emiliani, S., Benkirane, M., Kiernan, R.E. EMBO J. (2002) [Pubmed]
  16. Direct p53 transcriptional repression: in vivo analysis of CCAAT-containing G2/M promoters. Imbriano, C., Gurtner, A., Cocchiarella, F., Di Agostino, S., Basile, V., Gostissa, M., Dobbelstein, M., Del Sal, G., Piaggio, G., Mantovani, R. Mol. Cell. Biol. (2005) [Pubmed]
  17. p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Liu, L., Scolnick, D.M., Trievel, R.C., Zhang, H.B., Marmorstein, R., Halazonetis, T.D., Berger, S.L. Mol. Cell. Biol. (1999) [Pubmed]
  18. Interaction of histone acetylases and deacetylases in vivo. Yamagoe, S., Kanno, T., Kanno, Y., Sasaki, S., Siegel, R.M., Lenardo, M.J., Humphrey, G., Wang, Y., Nakatani, Y., Howard, B.H., Ozato, K. Mol. Cell. Biol. (2003) [Pubmed]
  19. The histone acetylase PCAF is a phorbol-ester-inducible coactivator of the IRF family that confers enhanced interferon responsiveness. Masumi, A., Wang, I.M., Lefebvre, B., Yang, X.J., Nakatani, Y., Ozato, K. Mol. Cell. Biol. (1999) [Pubmed]
  20. MDM2 mediates p300/CREB-binding protein-associated factor ubiquitination and degradation. Jin, Y., Zeng, S.X., Lee, H., Lu, H. J. Biol. Chem. (2004) [Pubmed]
  21. Site-specific acetylation of the fetal globin activator NF-E4 prevents its ubiquitination and regulates its interaction with the histone deacetylase, HDAC1. Zhao, Q., Cumming, H., Cerruti, L., Cunningham, J.M., Jane, S.M. J. Biol. Chem. (2004) [Pubmed]
  22. Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP. Li, S., Aufiero, B., Schiltz, R.L., Walsh, M.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  23. Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Spilianakis, C., Papamatheakis, J., Kretsovali, A. Mol. Cell. Biol. (2000) [Pubmed]
  24. Fluorescence analysis of a dynamic loop in the PCAF/GCN5 histone acetyltransferase. Zheng, Y., Mamdani, F., Toptygin, D., Brand, L., Stivers, J.T., Cole, P.A. Biochemistry (2005) [Pubmed]
  25. Application of a fluorescent histone acetyltransferase assay to probe the substrate specificity of the human p300/CBP-associated factor. Trievel, R.C., Li, F.Y., Marmorstein, R. Anal. Biochem. (2000) [Pubmed]
  26. MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)-mediated p53 acetylation. Jin, Y., Zeng, S.X., Dai, M.S., Yang, X.J., Lu, H. J. Biol. Chem. (2002) [Pubmed]
  27. Coactivator p300 acetylates the interferon regulatory factor-2 in U937 cells following phorbol ester treatment. Masumi, A., Ozato, K. J. Biol. Chem. (2001) [Pubmed]
  28. Acetylation of interferon regulatory factor-7 by p300/CREB-binding protein (CBP)-associated factor (PCAF) impairs its DNA binding. Caillaud, A., Prakash, A., Smith, E., Masumi, A., Hovanessian, A.G., Levy, D.E., Marié, I. J. Biol. Chem. (2002) [Pubmed]
  29. The histone acetyltransferase activity of PCAF cooperates with the brahma/SWI2-related protein BRG-1 in the activation of the enhancer A of the MHC class I promoter. Brockmann, D., Lehmkühler, O., Schmücker, U., Esche, H. Gene (2001) [Pubmed]
  30. The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily. Vassilev, A., Yamauchi, J., Kotani, T., Prives, C., Avantaggiati, M.L., Qin, J., Nakatani, Y. Mol. Cell (1998) [Pubmed]
  31. Regulation of transcription factor YY1 by acetylation and deacetylation. Yao, Y.L., Yang, W.M., Seto, E. Mol. Cell. Biol. (2001) [Pubmed]
  32. Regulation of ERK1 gene expression by coactivator proteins. Chu, B.Y., Tran, K., Ku, T.K., Crowe, D.L. Biochem. J. (2005) [Pubmed]
  33. Specific acetylation of chromosomal protein HMG-17 by PCAF alters its interaction with nucleosomes. Herrera, J.E., Sakaguchi, K., Bergel, M., Trieschmann, L., Nakatani, Y., Bustin, M. Mol. Cell. Biol. (1999) [Pubmed]
  34. Mammalian GCN5 and P/CAF acetyltransferases have homologous amino-terminal domains important for recognition of nucleosomal substrates. Xu, W., Edmondson, D.G., Roth, S.Y. Mol. Cell. Biol. (1998) [Pubmed]
  35. Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Fu, M., Wang, C., Wang, J., Zhang, X., Sakamaki, T., Yeung, Y.G., Chang, C., Hopp, T., Fuqua, S.A., Jaffray, E., Hay, R.T., Palvimo, J.J., Jänne, O.A., Pestell, R.G. Mol. Cell. Biol. (2002) [Pubmed]
  36. Molecular interaction of retinoic acid receptors with coregulators PCAF and RIP140. Chen, Y., Hu, X., Wei, L.N. Mol. Cell. Endocrinol. (2004) [Pubmed]
  37. Coactivators p300 and PCAF physically and functionally interact with the foamy viral trans-activator. Bannert, H., Muranyi, W., Ogryzko, V.V., Nakatani, Y., Flügel, R.M. BMC Mol. Biol. (2004) [Pubmed]
  38. The diurnal rhythm of adrenocorticotropic hormone secretion in the assessment of the adequacy of replacement therapy in primary chronic adrenal failure. Fadeev, V.V., Gitel, E.P., Mel'nichenko, G.A. Neurosci. Behav. Physiol. (2001) [Pubmed]
  39. Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group Study. Falkson, G., Gelman, R.S., Tormey, D.C., Falkson, C.I., Wolter, J.M., Cummings, F.J. J. Clin. Oncol. (1987) [Pubmed]
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