HTATIP (HIV-1 Tat interacting protein, 60kDa)

Identity

Other names	Tip60
	Tip
	60kDa Tat interacting protein
	HIV-1 Tat interacting protein
	cPLA(2) interacting protein
	iTip60
	PLIP/Tip60b
	Tip60a
	Esa1
	Hs.6364
HGNC	KAT5
Location	11q13.1
Location_base_pair	Starts at 65236065 and ends at 65243651 bp from pter (hg18-Mar_2006).

DNA/RNA

Description	The HTATIP gene consists of 14 exons. 7,586 bases.
Transcription	The predominant mRNA transcribed from this gene is 2,229 bp long. This is actually the isoform 2 of HTATIP. Two others isoforms generated by alternative splicing have been described: Isoform 1 retains the alternatively spliced intron 1. Isoform 3 lacks exon 5.
Pseudogene	No pseudogene is currently known.

Protein

Description	The Tip60 protein (isoform 2) is 513 amino acids long and its molecular weight is about 60 kDa. It was cloned and characterized in 1996 thanks to its interaction with the HIV-1 transactivator Tat protein. Isoform 1 produces a 546 amino acids long protein. Isoform 3 produces a 461 amino acids long protein. A novel isoform, Tip55, encodes a novel splicing variant corresponding to 103 amino acids of the C-terminus. The domain architectures of human TIP60 is similar to yeast Esa1 protein and consist of a chromodomain and a MYST domain harboring a zinc finger and an Acetyl-CoA binding site.
Expression	Tip60 is ubiquitously expressed. In mouse adult tissues Tip60 is expressed in the following decreasing order of intensity: testis, heart, brain, kidney, liver, lung, with little to no expression in spleen and skeletal muscle . In human, Tip60 (Isoform 2) and PLIP (Isoform 3) are expressed in human heart, kidney and brain tissue. With a half-life of approximately 30 minutes, Tip60 is very unstable. In normal conditions, the proteasome pathway permits to maintain low protein levels. Tip60 is ubiquitinated and targeted to proteasome-mediated degradation by Mdm2 but also by p300-associated E4 ubiquitin ligase. Tip60 is stabilized after DNA damage, and accumulates in cells. Moreover, Tip60 is the target of several post-translational modifications such as phosphorylation on serine 86 and 90 by cdc2 but also acetylation by p300/CBP acetyltransferases. Acetylation by p300/CBP occurs in the zinc finger of Tip60 but consequences of this modification are currently not known. Finally, a recent report shows that Tip60 is sumoylated at lysines 430 and 451 via Ubc9. No data are available about regulation of the Tip60 promoter.
Localisation	Tip60 (Isoform 2) is nuclear. PLIP (Isoform 3) is nuclear but also cytoplasmic.
Function	Tip60 is a Histone Acetyltransferase (HAT), which belongs to the MYST family. It participates in a multimolecular complex: The Tip60 complex, which contains proteins such as p400, Tip49a and Tip49b . Within this complex, Tip60 exerts its HAT activity on nucleosomal histone H4. Tip60 is involved in various cellular mechanisms: In transcription: Tip60 acts as a coactivator. Indeed, Tip60 is able to interact with transcription factors, such as E2F-1 or c-Myc. Tip60 can be recruited to Myc and E2F-1 target promoters and enhances Myc transactivation. It also acetylates histone H4 on several E2F responsive genes. Moreover Tip60 was found to be involved in nuclear receptor (NR) signaling and to be a NR-coregulator. In apoptosis and cell cycle arrest: Tip60 can interact with and acetylate the tumor suppressor p53. It enhances p53 binding to pro-apoptotic target genes like PUMA, Bax or Fas. Moreover, Tip60 is also required for cell growth arrest via the p21-dependent pathway. In DNA repair: Tip60 is involved in double strand breaks (DSB) repair. Interacting and acetylating ATM, Tip60 participates in DNA damage signaling. But, Tip60 is also involved directly in DSB repair since it is recruited, with TRRAP, to the DSB site. Tip60 interacts with the chromatin surrounding sites of DSBs and this recruitment is responsible for hyperacetylation of histone H4.
Homology	Tip60 CHROMO domain has been identified by sequence homology with the Heterochromatin-associated protein 1 (HP1) chromodomain, which recognizes methylated lysines. It also harbors the MYST domain, which is highly conserved from yeast to human. Homologs in other species: S. Cerevisae: Esa1 D. Melanogaster: DmeI/Tip60 M. musculus: Htatip R. norvegicus: Htatip Predicted: P.troglodytes: HTATIP M.mulatta: HTATIP

Mutations

Note	No mutation in Tip60 protein has been currently described.

Implicated in

Entity	Acquired Immunodeficiency Syndrome (AIDS)
Disease	Tip60 interacts with the HIV-1 transactivator Tat and this interaction inhibits Tip60 HAT activity. Moreover, in Jurkat cells, Tat enhances Tip60 turnover since it uses the p300/CBP-associated E4-type ubiquitin-ligase activity to induce polyubiquitynation and degradation of Tip60. This targeting by Tat induces an impairment of Tip60-dependent apoptosis after DNA damage.
Entity	Neurodegenerative diseases
Entity	Alzheimer¹s disease
Disease	In the nucleus of human H4 neuroglioma cells, TIP60 can interact with a free carboxyl-terminal intracellular fragment, APP-CT, which is generated by the cleavage of the Amyloid precursor protein APP by a gamma-secretase. This fragment induces apoptosis of neuroglioma and this cell death is enhanced when a wild type form of Tip60 is transfected. Thus Tip60 might play a role in Alzheimer¹s disease neurodegeneration.
Entity	Spinocerebellar ataxia type-1
Disease	TIP60 participates in a complex with ATXN1 and ROR-alpha in a conditional transgenic mouse model of Spinocerebellar ataxia type-1 (SCA1), one of the nine inherited polyglutamine neurodegenerative diseases.
Entity	Cancers
Entity	Prostate cancer
Disease	Immunohistochemistry experiments have shown that Tip60 accumulates in the nucleus of hormone-refractory prostate cancer compared to prostate hyperplasia and primary prostate cancer.
Entity	Lung cancer and colon cancer
Disease	Real time RT-PCR experiments have shown that Tip60 mRNA is under expressed in colon and lung carcinomas.
Entity	Skin cancer
Disease	The expression levels of TIP60 protein, analyzed by western blot, were found to be greater in skin tumors as compared to adjacent non-tumor-bearing skin in a skin cancer mouse model (K6/ODC mouse). Additionally, the interaction between Tip60 and E2F1 is enhanced in these tumors.
Entity	HTLV-1 induced leukemogenesis
Disease	Enhancement of c-Myc transforming activity by HTLV-1 p30II oncoprotein in HeLa cells requires TIP60 HAT activity.

External links

	Nomenclature
HGNC	KAT5   5275
Entrez_Gene	KAT5  10524  K(lysine) acetyltransferase 5
	Cards
Atlas	HTATIPID40893ch11q13
GeneCards	KAT5
Ensembl	KAT5 [Search_View]   ENSG00000172977 [Gene_View]
Genatlas	KAT5
GeneLynx	KAT5
eGenome	KAT5
euGene	10524
	Genomic and cartography
GoldenPath	KAT5  -  11q13.1   chr11:65236065-65243651 +  11q13   [Description]    (hg18-Mar_2006)
Ensembl	KAT5 - 11q13 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	KAT5
	Gene and transcription
Genbank	AB209813 [ ENTREZ ]
Genbank	AK130717 [ ENTREZ ]
Genbank	AK225100 [ ENTREZ ]
Genbank	AK226002 [ ENTREZ ]
Genbank	AK304664 [ ENTREZ ]
RefSeq	NM_006388 [ SRS ]    NM_006388 [ ENTREZ ]
RefSeq	NM_182709 [ SRS ]    NM_182709 [ ENTREZ ]
RefSeq	NM_182710 [ SRS ]    NM_182710 [ ENTREZ ]
RefSeq	AC_000054 [ SRS ]    AC_000054 [ ENTREZ ]
RefSeq	AC_000143 [ SRS ]    AC_000143 [ ENTREZ ]
RefSeq	NC_000011 [ SRS ]    NC_000011 [ ENTREZ ]
RefSeq	NT_033903 [ SRS ]    NT_033903 [ ENTREZ ]
RefSeq	NW_001838025 [ SRS ]    NW_001838025 [ ENTREZ ]
RefSeq	NW_925106 [ SRS ]    NW_925106 [ ENTREZ ]
AceView	KAT5 AceView - NCBI
Unigene	Hs.528299 [ SRS ]    Hs.528299 [ NCBI ]     HS528299 [ spliceNest ]
Fast-db	9932 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q561W3 [ SRS]    Q561W3 [ EXPASY ]     Q561W3 [ INTERPRO ]     Q561W3 [ UNIPROT ]
Interpro	IPR016181 Acyl_CoA_acyltransferase [ SRS ]    IPR016181 Acyl_CoA_acyltransferase [ EBI ]
Interpro	IPR000953 Chromodomain [ SRS ]    IPR000953 Chromodomain [ EBI ]
Interpro	IPR002717 MOZ_SAS [ SRS ]    IPR002717 MOZ_SAS [ EBI ]
Interpro	IPR011991 Wing_hlx_DNA_bd [ SRS ]    IPR011991 Wing_hlx_DNA_bd [ EBI ]
CluSTr	Q561W3
Pfam	PF01853 MOZ_SAS [ SRS ]    PF01853 MOZ_SAS [ Sanger ]    pfam01853 [ NCBI-CDD ]
Smart	SM00298 CHROMO [EMBL]
Blocks	Q561W3
HPRD	03245
	Protein Interaction databases
DIP	Q561W3
IntAct	Q561W3
	Polymorphism : SNP, mutations, diseases
OMIM	601409    [ map ]
GENECLINICS	601409
SNP	KAT5 [dbSNP-NCBI]
SNP	NM_006388 [SNP-NCI]
SNP	NM_182709 [SNP-NCI]
SNP	NM_182710 [SNP-NCI]
SNP	KAT5 [GeneSNPs - Utah]  KAT5] [HGBASE - SRS]
HAPMAP	KAT5 [HAPMAP]
HGMD	KAT5
	General knowledge
Family Browser	KAT5 [UCSC Family Browser]
SOURCE	NM_006388
SOURCE	NM_182709
SOURCE	NM_182710
SMD	Hs.528299
SAGE	Hs.528299
GO	chromatin [Amigo]  chromatin
GO	regulation of cell growth [Amigo]  regulation of cell growth
GO	chromatin binding [Amigo]  chromatin binding
GO	transcription coactivator activity [Amigo]  transcription coactivator activity
GO	histone acetyltransferase activity [Amigo]  histone acetyltransferase activity
GO	protein binding [Amigo]  protein binding
GO	nucleus [Amigo]  nucleus
GO	cytoplasm [Amigo]  cytoplasm
GO	double-strand break repair [Amigo]  double-strand break repair
GO	chromatin assembly or disassembly [Amigo]  chromatin assembly or disassembly
GO	transcription [Amigo]  transcription
GO	transcription from RNA polymerase II promoter [Amigo]  transcription from RNA polymerase II promoter
GO	zinc ion binding [Amigo]  zinc ion binding
GO	acyltransferase activity [Amigo]  acyltransferase activity
GO	chromatin modification [Amigo]  chromatin modification
GO	histone acetylation [Amigo]  histone acetylation
GO	transferase activity [Amigo]  transferase activity
GO	androgen receptor signaling pathway [Amigo]  androgen receptor signaling pathway
GO	NuA4 histone acetyltransferase complex [Amigo]  NuA4 histone acetyltransferase complex
GO	interspecies interaction between organisms [Amigo]  interspecies interaction between organisms
GO	positive regulation of transcription, DNA-dependent [Amigo]  positive regulation of transcription, DNA-dependent
GO	metal ion binding [Amigo]  metal ion binding
GO	androgen receptor binding [Amigo]  androgen receptor binding
BIOCARTA	Multi-step Regulation of Transcription by Pitx2    [Genes]
PubGene	KAT5
TreeFam	KAT5
CTD	10524 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	KAT5 Related clones (RZPD - Berlin)
	PubMed
PubMed	77 Pubmed reference(s) in Entrez

Bibliography

Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator.

Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G

Virology. 1996 ; 216 (2) : 357-366.

PMID 8607265

Tip60 is a nuclear hormone receptor coactivator.

Brady ME, Ozanne DM, Gaughan L, Waite I, Cook S, Neal DE, Robson CN

The Journal of biological chemistry. 1999 ; 274 (25) : 17599-17604.

PMID 10364196

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 ; 38 (27) : 8826-8830.

PMID 10393559

Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis.

Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y

Cell. 2000 ; 102 (4) : 463-473.

PMID 10966108

Identification of an alternatively spliced form of the Tat interactive protein (Tip60), Tip60(beta).

Ran Q, Pereira-Smith OM

Gene. 2000 ; 258 (1-2) : 141-146.

PMID 11111051

Tip60 is a co-activator specific for class I nuclear hormone receptors.

Gaughan L, Brady ME, Cook S, Neal DE, Robson CN

The Journal of biological chemistry. 2001 ; 276 (50) : 46841-46848.

PMID 11591700

PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production.

Sheridan AM, Force T, Yoon HJ, O'Leary E, Choukroun G, Taheri MR, Bonventre JV

Molecular and cellular biology. 2001 ; 21 (14) : 4470-4481.

PMID 11416127

Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor.

Gaughan L, Logan IR, Cook S, Neal DE, Robson CN

The Journal of biological chemistry. 2002 ; 277 (29) : 25904-25913.

PMID 11994312

The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells.

Kinoshita A, Whelan CM, Berezovska O, Hyman BT

The Journal of biological chemistry. 2002 ; 277 (32) : 28530-28536.

PMID 12032152

Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation.

Legube G, Linares LK, Lemercier C, Scheffner M, Khochbin S, Trouche D

The EMBO journal. 2002 ; 21 (7) : 1704-1712.

PMID 11927554

Characterization and expression of the mouse tat interactive protein 60 kD (TIP60) gene.

McAllister D, Merlo X, Lough J

Gene. 2002 ; 289 (1-2) : 169-176.

PMID 12036595

MYC recruits the TIP60 histone acetyltransferase complex to chromatin.

Frank SR, Parisi T, Taubert S, Fernandez P, Fuchs M, Chan HM, Livingston DM, Amati B

EMBO reports. 2003 ; 4 (6) : 575-580.

PMID 12776177

Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development.

Halkidou K, Gnanapragasam VJ, Mehta PB, Logan IR, Brady ME, Cook S, Leung HY, Neal DE, Robson CN

Oncogene. 2003 ; 22 (16) : 2466-2477.

PMID 12717424

Identification of a larger form of the histone acetyl transferase Tip60.

Legube G, Trouche D

Gene. 2003 ; 310 : 161-168.

PMID 12801643

Tip60 acetyltransferase activity is controlled by phosphorylation.

Lemercier C, Legube G, Caron C, Louwagie M, Garin J, Trouche D, Khochbin S

The Journal of biological chemistry. 2003 ; 278 (7) : 4713-4718.

PMID 12468530

A large-scale RNAi screen in human cells identifies new components of the p53 pathway.

Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds A, Heimerikx M, Kerkhoven RM, Madiredjo M, Nijkamp W, Weigelt B, Agami R, Ge W, Cavet G, Linsley PS, Beijersbergen RL, Bernards R

Nature. 2004 ; 428 (6981) : 431-437.

PMID 15042092

Role of the histone acetyl transferase Tip60 in the p53 pathway.

Legube G, Linares LK, Tyteca S, Caron C, Scheffner M, Chevillard-Briet M, Trouche D

The Journal of biological chemistry. 2004 ; 279 (43) : 44825-44833.

PMID 15310756

E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1.

Taubert S, Gorrini C, Frank SR, Parisi T, Fuchs M, Chan HM, Livingston DM, Amati B

Molecular and cellular biology. 2004 ; 24 (10) : 4546-4556.

PMID 15121871

A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions.

Awasthi S, Sharma A, Wong K, Zhang J, Matlock EF, Rogers L, Motloch P, Takemoto S, Taguchi H, Cole MD, Lˆºscher B, Dittrich O, Tagami H, Nakatani Y, McGee M, Girard AM, Gaughan L, Robson CN, Monnat RJ Jr, Harrod R

Molecular and cellular biology. 2005 ; 25 (14) : 6178-6198.

PMID 15988028

HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses.

Col E, Caron C, Chable-Bessia C, Legube G, Gazzeri S, Komatsu Y, Yoshida M, Benkirane M, Trouche D, Khochbin S

The EMBO journal. 2005 ; 24 (14) : 2634-2645.

PMID 16001085

A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM.

Sun Y, Jiang X, Chen S, Fernandes N, Price BD

Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (37) : 13182-13187.

PMID 16141325

Tip60 protein isoforms and altered function in skin and tumors that overexpress ornithine decarboxylase.

Hobbs CA, Wei G, DeFeo K, Paul B, Hayes CS, Gilmour SK

Cancer research. 2006 ; 66 (16) : 8116-8122.

PMID 16912189

Co-activation of atrial natriuretic factor promoter by Tip60 and serum response factor.

Kim MS, Merlo X, Wilson C, Lough J

The Journal of biological chemistry. 2006 ; 281 (22) : 15082-15089.

PMID 16597624

New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas.

LLeonart ME, Vidal F, Gallardo D, Diaz-Fuertes M, Rojo F, Cuatrecasas M, Lˆ„pez-Vicente L, Kondoh H, Blanco C, Carnero A, Ramˆ„n y Cajal S

Oncology reports. 2006 ; 16 (3) : 603-608.

PMID 16865262

Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks.

Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ, Herceg Z

Nature cell biology. 2006 ; 8 (1) : 91-99.

PMID 16341205

RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.

Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, Lysholm A, Burright E, Zoghbi HY, Clark HB, Andresen JM, Orr HT

Cell. 2006 ; 127 (4) : 697-708.

PMID 17110330

Acetylation of the p53 DNA-binding domain regulates apoptosis induction.

Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS, McMahon SB

Molecular cell. 2006 ; 24 (6) : 841-851.

PMID 17189187

Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.

Tang Y, Luo J, Zhang W, Gu W

Molecular cell. 2006 ; 24 (6) : 827-839.

PMID 17189186

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

The EMBO journal. 2006 ; 25 (8) : 1680-1689.

PMID 16601686

Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response.

Cheng Z, Ke Y, Ding X, Wang F, Wang H, Ahmed K, Liu Z, Xu Y, Aikhionbare F, Yan H, Liu J, Xue Y, Powell M, Liang S, Reddy SE, Hu R, Huang H, Jin C, Yao X

Oncogene. 2008 ; 27 (7) : 931-941.

PMID 17704809

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Contributor(s)

Written	10-2007	Lise Mattera
		Dr Trouche Team, LBCMCP, UMR 5088 CNRS, 118 route de Narbonne, 31062 Toulouse cedex 9, France

Citation

This paper should be referenced as such :

Mattera L . HTATIP (HIV-1 Tat interacting protein, 60kDa). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HTATIPID40893ch11q13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Sat Oct 11 12:52:15 2008