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HTATIP2 (HIV-1 Tat interactive protein 2, 30kDa)

Written2009-03Jian Zhao
International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China

(Note : for Links provided by Atlas : click)


Other aliasCC3
LocusID (NCBI) 10553
Atlas_Id 40894
Location 11p15.1  [Link to chromosome band 11p15]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
HTATIP2 (11p15.1) / CA1 (8q21.2)HTATIP2 (11p15.1) / SUPT20H (13q13.3)
Note HTATIP2, also called TIP30, is a transcriptional cofactor that enhances Tat-mediated transcription.


  Genomic structure of published HTATIP2 alternatively spliced transcripts. Boxes indicate exons with coding regions in green. Red boxes indicate UTRs.
Description The human HTATIP2 gene has 6 exons that span more than 2.5 kb of genomic sequence located on chromosome 11p15.1.
Transcription HTATIP2 has four types of transcripts with 1.5 kb, 1.4 kb, 1.7 kb and 1.4 kb and they encode the same protein, 242aa, as a result of alternative splicing. And a small type of HTATIP2 isoform is 0.78 kb composed of 2 exons coding a 133aa protein.
Pseudogene None.


  Structure model of HTATIP2/TIP30. Serine-132, tyrosine-143 and lysine-147, which correspond to the catalytically active residues in SDRs and NADPH are shown. The a-helices E and F normally involved in a dimer interface are labelled (Baker et al., 2000).
Description HTATIP2 includes isoform a and isoform b, both of which contain 242aa, and isoform c, 131aa. HTATIP2 can interact with the N-terminal trans-activation domain of HIV-tat directly as 30kDa Tat-interacting protein, to activate the HIV-1 promoter (Xiao et al., 1998), and with an ERa-interacting coactivator CIA to repress the expression of c-myc (Jiang et al., 2004). It is a member of the short-chain dehydrogenases/reductases (SDR) family (Baker et al., 2000) and have a cavity of NADPH binding site in its structure (El Omari et al., 2005). HTATIP2 has Ser/Thr protein kinase activity, which can undergo autophosphorylation, and phosphorylates the heptapeptide repeats of the C-terminal domain of the largest RNA polymerase II subunit in a tat-dependent manner. HTATIP2 binds directly to the karyopherins of the importin beta family in a RanGTP-insensitive manner and associates with nucleoporins in vivo (King and Shtivelman, 2004).
Expression HTATIP2 is an evolutionary conserved gene that is expressed ubiquitously in human tissues, while it is down-expressed in many tumors tissues, such as prostate, colon, liver, lung and breast cancers (Hewitt et al., 2000; Jiang et al., 2007; Lee et al., 2004; Varambally et al., 2002).
Localisation HTATIP2 protein was found predominantly in the membrane and nuclear fractions but not in the particulate free cytoplasmic fraction (Whitman et al., 2000).
Function The HTATIP2 gene is a tumor susceptibility gene, which is associated with the suppression of metastasis in small cell lung cancer (SCLC) (Shtivelman, 1997), hepatocarcinoma (Ito et al., 2003). HTATIP2 interacts with an Estrogen Receptor alpha-interacting coactivator CIA (coactivator independent of AF-2 function), to repress the expression of c-myc gene, and also associated with ets-1 to inhibit osteopontin transcription in human hepatocellular carcinoma (Zhao et al., 2008b). HTATIP2 forms a RanGTP-resistant complex with importins to inhibit nuclear import and induce apoptosis (King and Shtivelman, 2004). HTATIP2 also induces apoptosis under oxidative stress through stabilization of p53 mRNA (Zhao et al., 2008a).
Homology HTATIP2 encodes a protein whose sequence is highly conserved in evolution, with homologous genes being present in Caenorhabditis elegans, Saccharomyces cerevisiae, Escherichia coli (Whitman et al., 2000), Branchiostoma belcheri (Wang et al., 2008), and Mus musculus.


Note HTATIP2 mutant derived from hepatocellular carcinoma specimens promotes growth of HepG2 cells (Jiang et al., 2007).
  The red amino acids are mutated into other one, as schematic representation (Jiang et al., 2007).
Somatic There are two types of HTATIP2 mutation, G134V and R106H, in hepatocellular carcinoma specimens (Jiang et al., 2007).

Implicated in

Entity Various carcinomas
Disease HTATIP2 reported to be down-regulated in some kinds of cancers, such as lung cancer (NicAmhlaoibh and Shtivelman, 2001), hepatocellular carcinoma (Zhao et al., 2008), gastric cancer (Li et al., 2009), prostate cancer (Zhang et al., 2008), breast carcinoma (Zhang et al., 2005; Zhao et al., 2007).
Entity Multiple sclerosis (MS)
Disease Oligodendrocyte precursor cells (OPCs) presist near the demyelinated axons arising in MS but inefficiently differentiate into oligodendrocytes and remyelinate these axons. Abnormal expression of HTATIP2, a direct inhibitor of Importin, is observed in these OPCs. Overexpression of HTATIP2 in a rat OPC cell line resulted in cytoplasmic entrapment of NICD and arrest of differentiation upon stimulation with Contactin- Fc.


Three-dimensional model of human TIP30, a coactivator for HIV-1 Tat-activated transcription, and CC3, a protein associated with metastasis suppression.
Baker ME, Yan L, Pear MR.
Cell Mol Life Sci. 2000 May;57(5):851-8.
PMID 10892349
Crystal structure of CC3 (TIP30): implications for its role as a tumor suppressor.
El Omari K, Bird LE, Nichols CE, Ren J, Stammers DK.
J Biol Chem. 2005 May 6;280(18):18229-36. Epub 2005 Feb 22.
PMID 15728189
Increased expression of tissue inhibitor of metalloproteinases type 1 (TIMP-1) in a more tumourigenic colon cancer cell line.
Hewitt RE, Brown KE, Corcoran M, Stetler-Stevenson WG.
J Pathol. 2000 Dec;192(4):455-9.
PMID 11113862
TIP30 deficiency increases susceptibility to tumorigenesis.
Ito M, Jiang C, Krumm K, Zhang X, Pecha J, Zhao J, Guo Y, Roeder RG, Xiao H.
Cancer Res. 2003 Dec 15;63(24):8763-7.
PMID 14695192
TIP30 interacts with an estrogen receptor alpha-interacting coactivator CIA and regulates c-myc transcription.
Jiang C, Ito M, Piening V, Bruck K, Roeder RG, Xiao H.
J Biol Chem. 2004 Jun 25;279(26):27781-9. Epub 2004 Apr 8.
PMID 15073177
TIP30 mutant derived from hepatocellular carcinoma specimens promotes growth of HepG2 cells through up-regulation of N-cadherin.
Jiang C, Pecha J, Hoshino I, Ankrapp D, Xiao H.
Cancer Res. 2007 Apr 15;67(8):3574-82.
PMID 17440068
Inhibition of nuclear import by the proapoptotic protein CC3.
King FW, Shtivelman E.
Mol Cell Biol. 2004 Aug;24(16):7091-101.
PMID 15282309
CC3/TIP30 expression was strongly associated with HER-2/NEU status in breast cancer.
Lee LW, Zhang DH, Lee KT, Koay ES, Hewitt RE.
Ann Acad Med Singapore. 2004 Sep;33(5 Suppl):S30-2.
PMID 15651195
Reduction of TIP30 correlates with poor prognosis of gastric cancer patients and its restoration drastically inhibits tumor growth and metastasis.
Li X, Zhang Y, Cao S, Chen X, Lu Y, Jin H, Sun S, Chen B, Liu J, Ding J, Wu K, Fan D.
Int J Cancer. 2009 Feb 1;124(3):713-21.
PMID 18972434
Methylation of Tip30 promoter is associated with poor prognosis in human hepatocellular carcinoma.
Lu B, Ma Y, Wu G, Tong X, Guo H, Liang A, Cong W, Liu C, Wang H, Wu M, Zhao J, Guo Y.
Clin Cancer Res. 2008 Nov 15;14(22):7405-12.
PMID 19010857
Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis.
Nakahara J, Kanekura K, Nawa M, Aiso S, Suzuki N.
J Clin Invest. 2009 Jan;119(1):169-81.
PMID 19104151
Metastasis suppressor CC3 inhibits angiogenic properties of tumor cells in vitro.
NicAmhlaoibh R, Shtivelman E.
Oncogene. 2001 Jan 11;20(2):270-5.
PMID 11313954
A link between metastasis and resistance to apoptosis of variant small cell lung carcinoma.
Shtivelman E.
Oncogene. 1997 May 8;14(18):2167-73.
PMID 9174052
The polycomb group protein EZH2 is involved in progression of prostate cancer.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM.
Nature. 2002 Oct 10;419(6907):624-9.
PMID 12374981
Cloning, expression, purification, and characterization of AmphiTip30, a member of short-chain dehydrogenases/reductases family from the amphioxus Branchiostoma belcheri tsingtauense.
Wang S, Zhao B, Zhang S, Ji H.
Protein Expr Purif. 2008 Jan;57(1):63-71. Epub 2007 Sep 14.
PMID 17950618
Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis.
Whitman S, Wang X, Shalaby R, Shtivelman E.
Mol Cell Biol. 2000 Jan;20(2):583-93.
PMID 10611237
A cofactor, TIP30, specifically enhances HIV-1 Tat-activated transcription.
Xiao H, Tao Y, Greenblatt J, Roeder RG.
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2146-51.
PMID 9482853
Overexpression of CC3/TIP30 is associated with HER-2/neu status in breast cancer.
Zhang DH, Wong LL, Tai LK, Koay ES, Hewitt RE.
J Cancer Res Clin Oncol. 2005 Sep;131(9):603-8. Epub 2005 Oct 20.
PMID 15931508
TIP30 is associated with progression and metastasis of prostate cancer.
Zhang H, Zhang Y, Duan HO, Kirley SD, Lin SX, McDougal WS, Xiao H, Wu CL.
Int J Cancer. 2008 Aug 15;123(4):810-6.
PMID 18528861
TIP30 induces apoptosis under oxidative stress through stabilization of p53 messenger RNA in human hepatocellular carcinoma.
Zhao J, Chen J, Lu B, Dong L, Wang H, Bi C, Wu G, Guo H, Wu M, Guo Y.
Cancer Res. 2008 Jun 1;68(11):4133-41.
PMID 18519672
Thirty-kilodalton Tat-interacting protein suppresses tumor metastasis by inhibition of osteopontin transcription in human hepatocellular carcinoma.
Zhao J, Lu B, Xu H, Tong X, Wu G, Zhang X, Liang A, Cong W, Dai J, Wang H, Wu M, Guo Y.
Hepatology. 2008 Jul;48(1):265-75.
PMID 18537194
TIP30/CC3 expression in breast carcinoma: relation to metastasis, clinicopathologic parameters, and P53 expression.
Zhao J, Ni H, Ma Y, Dong L, Dai J, Zhao F, Yan X, Lu B, Xu H, Guo Y.
Hum Pathol. 2007 Feb;38(2):293-8. Epub 2006 Nov 13.
PMID 17097132


This paper should be referenced as such :
Zhao, J
HTATIP2 (HIV-1 Tat interactive protein 2, 30kDa)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(2):137-140.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Lung: Translocations in Squamous Cell Carcinoma
t(8;11)(q21;p15) HTATIP2/CA1

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)10553
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
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indexed on : Thu Oct 18 17:39:11 CEST 2018

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