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Gene Review

KAT5  -  K(lysine) acetyltransferase 5

Homo sapiens

Synonyms: 60 kDa Tat-interactive protein, ESA1, HIV-1 Tat interactive protein, HTATIP, HTATIP1, ...
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Disease relevance of HTATIP


Psychiatry related information on HTATIP

  • Therefore, we examined the association between the BanI polymorphism of the cPLA2 gene and mood disorders [5].
  • In view of the presence of numerous inflammatory mediators and acute phase proteins in the Alzheimer's disease (AD) brain, localization of cPLA2 in AD brain was evaluated and compared to that observed in nonneurologically diseased controls [6].

High impact information on HTATIP


Chemical compound and disease context of HTATIP


Biological context of HTATIP

  • The histone acetyl transferase Tip60 (HTATIP) belongs to a multimolecular complex involved in the cellular response to DNA damage [15].
  • This modification, acetylation of lysine 120 (K120), occurs rapidly after DNA damage and is catalyzed by the MYST family acetyltransferases hMOF and TIP60 [16].
  • While Max lacks a transcription regulatory domain, the N terminus of Myc contains a transcription activation domain (TAD) that recruits cofactor complexes containing the histone acetyltransferases (HATs) GCN5 and Tip60 [17].
  • Our data suggest that GAS41 plays a role in repressing the p53 tumor suppressor pathway during the normal cell cycle by a TIP60-independent mechanism [18].
  • Like Tip60, PLIP cDNA includes the MYST domain containing a C2HC zinc finger and well-conserved similarities to acetyltransferases [19].

Anatomical context of HTATIP

  • Consistent with this hypothesis, Tip60 levels increased significantly upon UV irradiation of Jurkat cells [20].
  • PLIP expression, mediated by adenoviral gene transfer, potentiates serum deprivation-induced prostaglandin E(2) (PGE(2)) production and apoptosis in mouse mesangial cells from cPLA(2)(+/+) mice but not in mesangial cells derived from cPLA(2)(-/-) mice [19].
  • Both PLIP and Tip60 coimmunoprecipitate and colocalize with cPLA(2) within the nuclei of transfected COS cells [19].
  • We previously isolated the TRRAP/TIP60 complex from HeLa cells (Cai, Y., Jin, J., Tomomori-Sato, C., Sato, S., Sorokina, I., Parmely, T. J., Conaway, R. C., and Conaway, J. W. (2003) J. Biol. Chem. 278, 42733-42736) [21].
  • The downstream events include phosphorylation and activation of MAP kinase by MAPKK and subsequent phosphorylation and activation of cPLA2 (with its translocation to cell membranes), followed by stimulation of the AA cascade, which generates intracellular ROS and thereby activates NF-kappaB [22].

Associations of HTATIP with chemical compounds

  • PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production [19].
  • Both beta-boswellic acid and 3-O-acetyl-11-keto-boswellic acid (AKBA) markedly enhanced the release of arachidonic acid via cytosolic phospholipase A2 (cPLA2), whereas for generation of 12-hydro(pero)xyeicosatetraenoic acid [12-H(P)ETE], AKBA was less potent than beta-boswellic acid and was without effect at higher concentrations (> or =30 microM) [23].
  • CONCLUSIONS: Our findings reveal the novel mechanism of HIPK2 to restrain progression of human colon tumorigenesis, at least in part, by turning off cPLA2-dependent PGE2 generation [1].
  • As assessed by [3H]-arachidonic acid release, cells primed for 48 h with CB1093 (50 nM) showed enhanced cPLA2 activation in response to TNFalpha or ceramide [24].
  • An antisense oligonucleotide to cPLA2 and the cPLA2 inhibitor 4-bromophenacyl bromide significantly inhibited TNF-induced cytotoxicity [25].
  • Knockdown of Tip60 expression rendered cells sensitive to cisplatin but not to oxaliplatin, vincristine, and etoposide [26].

Physical interactions of HTATIP

  • ATM forms a stable complex with Tip60 through the conserved FATC domain of ATM [27].
  • Tip60 interacts with human interleukin-9 receptor alpha-chain [28].
  • Interestingly, the region in hIL-9alpha that binds Tip60 is adjacent to the site previously shown to interact with Stat3 [28].
  • The APP adaptor protein Jip1b also transported AICD to nuclei and docked it to Tip60, but AICD-Jip1b-Tip60 (AJT) complexes had different, speckle-like morphology [29].
  • Looking for the mechanisms involved in this process, we demonstrate that the histone acetyl transferase Tip60 directly interacts with RB and stimulates its degradation by the proteasome through acetylation of its C-terminus [30].
  • The PML3-TIP60 interaction is specific, since the region of TIP60 binding is not conserved in other PML isoforms [31].

Regulatory relationships of HTATIP

  • This is the first demonstration of which Tip60 represses STAT3 activity in part through the recruitment of HDAC7 [32].
  • The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells [33].
  • Tip60 inhibits activation of CREB protein by protein kinase A [34].
  • Our study provides novel insight into regulation of ATM activation by ATF2-dependent control of TIP60 stability and activity [35].
  • TIP60 markedly enhanced p73beta binding affinity to MDM2 and physically associated with MDM2 through its zinc finger domain, which is specifically localized in the nucleus [36].

Other interactions of HTATIP

  • Instead, the HAT activity of the ATM-Tip60 complex is specifically activated by DNA damage [27].
  • We report here that mGCN5/PCAF and TIP60 acetylate c-MYC in vivo [37].
  • Moreover, E2F-dependent recruitment of Tip60 to chromatin occurred in late G(1) following serum stimulation [38].
  • Finally, analogous to yeast, a recombinant trimeric complex formed by Tip60, EPC1, and ING3 is sufficient to reconstitute robust nucleosomal HAT activity in vitro [39].
  • GAS41 is a common subunit of the TIP60 and SRCAP complexes and is essential for cell growth and viability [18].

Analytical, diagnostic and therapeutic context of HTATIP


  1. Homeodomain-interacting protein kinase-2 restrains cytosolic phospholipase A2-dependent prostaglandin E2 generation in human colorectal cancer cells. D'Orazi, G., Sciulli, M.G., Di Stefano, V., Riccioni, S., Frattini, M., Falcioni, R., Bertario, L., Sacchi, A., Patrignani, P. Clin. Cancer Res. (2006) [Pubmed]
  2. Control of the histone-acetyltransferase activity of Tip60 by the HIV-1 transactivator protein, Tat. Creaven, M., Hans, F., Mutskov, V., Col, E., Caron, C., Dimitrov, S., Khochbin, S. Biochemistry (1999) [Pubmed]
  3. Expression and function of androgen receptor coactivators in prostate cancer. Culig, Z., Comuzzi, B., Steiner, H., Bartsch, G., Hobisch, A. J. Steroid Biochem. Mol. Biol. (2004) [Pubmed]
  4. Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway. Hejna, J., Holtorf, M., Hines, J., Mathewson, L., Hemphill, A., Al-Dhalimy, M., Olson, S.B., Moses, R.E. J. Biol. Chem. (2008) [Pubmed]
  5. BanI polymorphism of the cytosolic phospholipase A2 gene and mood disorders in the Korean population. Pae, C.U., Yu, H.S., Kim, J.J., Lee, C.U., Lee, S.J., Lee, K.U., Jun, T.Y., Paik, I.H., Serretti, A., Lee, C. Neuropsychobiology (2004) [Pubmed]
  6. Cytosolic phospholipase A2 (cPLA2) immunoreactivity is elevated in Alzheimer's disease brain. Stephenson, D.T., Lemere, C.A., Selkoe, D.J., Clemens, J.A. Neurobiol. Dis. (1996) [Pubmed]
  7. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. Baek, S.H., Ohgi, K.A., Rose, D.W., Koo, E.H., Glass, C.K., Rosenfeld, M.G. Cell (2002) [Pubmed]
  8. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Ikura, T., Ogryzko, V.V., Grigoriev, M., Groisman, R., Wang, J., Horikoshi, M., Scully, R., Qin, J., Nakatani, Y. Cell (2000) [Pubmed]
  9. Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism. Dessen, A., Tang, J., Schmidt, H., Stahl, M., Clark, J.D., Seehra, J., Somers, W.S. Cell (1999) [Pubmed]
  10. cPLA2 is phosphorylated and activated by MAP kinase. Lin, L.L., Wartmann, M., Lin, A.Y., Knopf, J.L., Seth, A., Davis, R.J. Cell (1993) [Pubmed]
  11. Hydrogen peroxide generated at the level of mitochondria in response to peroxynitrite promotes U937 cell death via inhibition of the cytoprotective signalling mediated by cytosolic phospholipase A2. Tommasini, I., Sestili, P., Guidarelli, A., Cantoni, O. Cell Death Differ. (2004) [Pubmed]
  12. Independent folding and ligand specificity of the C2 calcium-dependent lipid binding domain of cytosolic phospholipase A2. Nalefski, E.A., McDonagh, T., Somers, W., Seehra, J., Falke, J.J., Clark, J.D. J. Biol. Chem. (1998) [Pubmed]
  13. Cytosolic phospholipase A2 is coupled to muscarinic receptors in the human astrocytoma cell line 1321N1: characterization of the transducing mechanism. Bayon, Y., Hernandez, M., Alonso, A., Nuñez, L., Garcia-Sancho, J., Leslie, C., Sanchez Crespo, M., Nieto, M.L. Biochem. J. (1997) [Pubmed]
  14. Differential stimulation of cytosolic phospholipase A2 by bradykinin in human cystic fibrosis cell lines. Berguerand, M., Klapisz, E., Thomas, G., Humbert, L., Jouniaux, A.M., Olivier, J.L., Béréziat, G., Masliah, J. Am. J. Respir. Cell Mol. Biol. (1997) [Pubmed]
  15. Tip60 and p400 are both required for UV-induced apoptosis but play antagonistic roles in cell cycle progression. Tyteca, S., Vandromme, M., Legube, G., Chevillard-Briet, M., Trouche, D. EMBO J. (2006) [Pubmed]
  16. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Sykes, S.M., Mellert, H.S., Holbert, M.A., Li, K., Marmorstein, R., Lane, W.S., McMahon, S.B. Mol. Cell (2006) [Pubmed]
  17. Dual regulation of c-Myc by p300 via acetylation-dependent control of Myc protein turnover and coactivation of Myc-induced transcription. Faiola, F., Liu, X., Lo, S., Pan, S., Zhang, K., Lymar, E., Farina, A., Martinez, E. Mol. Cell. Biol. (2005) [Pubmed]
  18. GAS41 is required for repression of the p53 tumor suppressor pathway during normal cellular proliferation. Park, J.H., Roeder, R.G. Mol. Cell. Biol. (2006) [Pubmed]
  19. PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production. Sheridan, A.M., Force, T., Yoon, H.J., O'Leary, E., Choukroun, G., Taheri, M.R., Bonventre, J.V. Mol. Cell. Biol. (2001) [Pubmed]
  20. Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation. Legube, G., Linares, L.K., Lemercier, C., Scheffner, M., Khochbin, S., Trouche, D. EMBO J. (2002) [Pubmed]
  21. The mammalian YL1 protein is a shared subunit of the TRRAP/TIP60 histone acetyltransferase and SRCAP complexes. Cai, Y., Jin, J., Florens, L., Swanson, S.K., Kusch, T., Li, B., Workman, J.L., Washburn, M.P., Conaway, R.C., Conaway, J.W. J. Biol. Chem. (2005) [Pubmed]
  22. Pertussis toxin-sensitive G proteins as mediators of the signal transduction pathways activated by cytomegalovirus infection of smooth muscle cells. Shibutani, T., Johnson, T.M., Yu, Z.X., Ferrans, V.J., Moss, J., Epstein, S.E. J. Clin. Invest. (1997) [Pubmed]
  23. Boswellic acids stimulate arachidonic acid release and 12-lipoxygenase activity in human platelets independent of Ca2+ and differentially interact with platelet-type 12-lipoxygenase. Poeckel, D., Tausch, L., Kather, N., Jauch, J., Werz, O. Mol. Pharmacol. (2006) [Pubmed]
  24. Potentiation by vitamin D analogs of TNFalpha and ceramide-induced apoptosis in MCF-7 cells is associated with activation of cytosolic phospholipase A2. Pirianov, G., Danielsson, C., Carlberg, C., James, S.Y., Colston, K.W. Cell Death Differ. (1999) [Pubmed]
  25. 1,25-Dihydroxyvitamin D3 protects human leukemic cells from tumor necrosis factor-induced apoptosis via inactivation of cytosolic phospholipase A2. Wu, Y.L., Jiang, X.R., Lillington, D.M., Allen, P.D., Newland, A.C., Kelsey, S.M. Cancer Res. (1998) [Pubmed]
  26. Tip60 is regulated by circadian transcription factor clock and is involved in cisplatin resistance. Miyamoto, N., Izumi, H., Noguchi, T., Nakajima, Y., Ohmiya, Y., Shiota, M., Kidani, A., Tawara, A., Kohno, K. J. Biol. Chem. (2008) [Pubmed]
  27. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Sun, Y., Jiang, X., Chen, S., Fernandes, N., Price, B.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  28. Tip60 interacts with human interleukin-9 receptor alpha-chain. Sliva, D., Zhu, Y.X., Tsai, S., Kamine, J., Yang, Y.C. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  29. The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. von Rotz, R.C., Kohli, B.M., Bosset, J., Meier, M., Suzuki, T., Nitsch, R.M., Konietzko, U. J. Cell. Sci. (2004) [Pubmed]
  30. p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation. Leduc, C., Claverie, P., Eymin, B., Col, E., Khochbin, S., Brambilla, E., Gazzeri, S. Oncogene (2006) [Pubmed]
  31. PML3 Orchestrates the Nuclear Dynamics and Function of TIP60. Wu, Q., Hu, H., Lan, J., Emenari, C., Wang, Z., Chang, K.S., Huang, H., Yao, X. J. Biol. Chem. (2009) [Pubmed]
  32. Tip60 is a co-repressor for STAT3. Xiao, H., Chung, J., Kao, H.Y., Yang, Y.C. J. Biol. Chem. (2003) [Pubmed]
  33. The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells. Kinoshita, A., Whelan, C.M., Berezovska, O., Hyman, B.T. J. Biol. Chem. (2002) [Pubmed]
  34. Tip60 inhibits activation of CREB protein by protein kinase A. Gavaravarapu, S., Kamine, J. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  35. Regulation of TIP60 by ATF2 modulates ATM activation. Bhoumik, A., Singha, N., O'Connell, M.J., Ronai, Z.A. J. Biol. Chem. (2008) [Pubmed]
  36. TIP60 represses transcriptional activity of p73beta via an MDM2-bridged ternary complex. Kim, J.W., Song, P.I., Jeong, M.H., An, J.H., Lee, S.Y., Jang, S.M., Song, K.H., Armstrong, C.A., Choi, K.H. J. Biol. Chem. (2008) [Pubmed]
  37. The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60. Patel, J.H., Du, Y., Ard, P.G., Phillips, C., Carella, B., Chen, C.J., Rakowski, C., Chatterjee, C., Lieberman, P.M., Lane, W.S., Blobel, G.A., McMahon, S.B. Mol. Cell. Biol. (2004) [Pubmed]
  38. E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Taubert, S., Gorrini, C., Frank, S.R., Parisi, T., Fuchs, M., Chan, H.M., Livingston, D.M., Amati, B. Mol. Cell. Biol. (2004) [Pubmed]
  39. Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans. Doyon, Y., Selleck, W., Lane, W.S., Tan, S., Côté, J. Mol. Cell. Biol. (2004) [Pubmed]
  40. Transcription regulation by the adaptor protein Fe65 and the nucleosome assembly factor SET. Telese, F., Bruni, P., Donizetti, A., Gianni, D., D'Ambrosio, C., Scaloni, A., Zambrano, N., Rosenfeld, M.G., Russo, T. EMBO Rep. (2005) [Pubmed]
  41. Unique targeting of cytosolic phospholipase A2 to plasma membranes mediated by the NADPH oxidase in phagocytes. Shmelzer, Z., Haddad, N., Admon, E., Pessach, I., Leto, T.L., Eitan-Hazan, Z., Hershfinkel, M., Levy, R. J. Cell Biol. (2003) [Pubmed]
  42. Failure to activate cytosolic phospholipase A2 causes TNF resistance in human leukemic cells. Wu, Y.L., Jiang, X.R., Newland, A.C., Kelsey, S.M. J. Immunol. (1998) [Pubmed]
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