Disease relevance of HTATIP

• We compared the gene expression of HIPK2 and cPLA2 in human colorectal cancer specimens by reverse transcriptase-PCR [1].
• HIPK2 mRNA levels were significantly higher in colorectal cancers of patients with familial adenomatous polyposis, which showed undetectable cPLA2 levels compared with sporadic colorectal cancer expressing cPLA2 [1].
• We postulate that the HIV-1 transactivator, Tat, in targeting Tip60 hinders the expression of cellular genes (such as Mn-SOD) which normally interfere with the efficient replication and propagation of the virus [2].
• Our data show that Tip60 does not significantly influence Tat-dependent transcriptional activation of the 5'-LTR of HIV, suggesting that its interaction with Tat affects some intrinsic cellular process [2].
• The AR coactivator Tip60, which is up-regulated by androgen ablation, is recruited to the promoter of the prostate-specific antigen gene in the absence of androgen in androgen-independent prostate cancer sublines [3].
• The coincident function of Tip60 and FANCD2 in one pathway is supported by the finding that depletion of Tip60 in Fanconi anemia cells does not increase sensitivity to DNA cross-links [4].

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

• Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein [7].
• These results indicate that the histone acetylase TIP60-containing complex plays a role in DNA repair and apoptosis [8].
• Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis [8].
• Here, we report the X-ray crystal structure of human cPLA2 at 2.5 A. cPLA2 consists of an N-terminal calcium-dependent lipid-binding/C2 domain and a catalytic unit whose topology is distinct from that of other lipases [9].
• Treatment of cells with agents that stimulate the release of arachidonic acid causes increased serine phosphorylation and activation of cytosolic phospholipase A2 (cPLA2) [10].

Chemical compound and disease context of HTATIP

• EXPERIMENTAL DESIGN: In the human colorectal cancer cell line, RKO, we studied the effect of RNA interference for HIPK2 (HIPK2i) on prostanoid biosynthesis, both in the absence and in the presence of the cPLA2 inhibitor arachidonyl trifluoromethyl ketone [1].
• We have studied the relationships existing between delayed formation of H2O2 and activation of cytosolic phospholipase A2 (cPLA2), events respectively promoting toxicity or survival in U937 cells exposed to peroxynitrite [11].
• NH2-terminal fragments of cPLA2 spanning the C2 domain were expressed as inclusion bodies in Escherichia coli, extracted with solvent to remove phospholipids, and refolded to yield a domain capable of binding phospholipid vesicles in a Ca(2+)-dependent manner [12].
• In summary, these data indicate the existence in the astrocytoma cell line 1321N1 of a pathway involving the cPLA2 which couples the release of arachidonate to the occupancy of receptors for a neurotransmitter, requires PKC activity and G-proteins and might operate in the absence of Ca2+ mobilization [13].
• As the binding of cPLA2 to membranes is Ca2+-dependent, the increased coupling to PLC could cause the hypersensitivity to bradykinin [14].

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

• We demonstrate by confocal microscopy and fluorescence resonance energy transfer analysis that APP-C58 translocates to the nucleus and forms a complex in the nucleus with the Tip60, independent of interactions with Fe65 [33].
• Two-step chromatin immunoprecipitation experiments demonstrate that a complex including Fe65/AICD/Tip60 and SET is associated with the KAI1 gene promoter [40].
• Coimmunoprecipitation experiments and double labeling immunofluorescence analysis demonstrated the unique colocalization of cPLA2 and the NADPH oxidase in plasma membranes of stimulated cells, in correlation with the kinetic burst of superoxide production [41].
• Both immunofluorescence microscopy and Western blotting of cell subcompartments demonstrated translocation of cPLA2 from the cytosol to the cell membrane in response to TNF [25].
• Immunoblot and reverse-transcriptase PCR demonstrated that cPLA2 expression was detectable at both transcriptional and translational levels in all leukemic cell lines studied, although CEM and CEM/VLB100 cells expressed cPLA2 mRNA and protein at lower levels [42].

References