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Gene Review

TIA1  -  TIA1 cytotoxic granule-associated RNA...

Homo sapiens

Synonyms: Nucleolysin TIA-1 isoform p40, RNA-binding protein TIA-1, T-cell-restricted intracellular antigen-1, TIA-1, WDM, ...
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Disease relevance of TIA1


High impact information on TIA1

  • Both natural and recombinant TIA-1 were found to induce DNA fragmentation in digitonin permeabilized thymocytes, suggesting that these molecules may be the granule components responsible for inducing apoptosis in CTL targets [5].
  • Sequence analysis reveals that the 40 kd TIA-1 isoform (rp40-TIA-1) is structurally related to the poly(A)-binding proteins, possessing three RNA-binding domains and a carboxy-terminal, glutamine-rich auxiliary domain [5].
  • (2007) reported that the steroid receptor coactivator-3 (SRC-3) has a novel cytoplasmic function: it activates the translational silencers TIA-1 and TIAR and thus inhibits the translation of proinflammatory cytokines [6].
  • Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition [7].
  • We report that the apoptosis-inducing protein TIA-1 promotes U1 snRNP binding to the 5' splice site of intron 6, which in turn facilitates exon definition by enhancing U2AF binding to the 3' splice site of intron 5 [7].

Chemical compound and disease context of TIA1


Biological context of TIA1

  • Phenotype showed positivity for CD2, CD3, CD45 and TIA1 and expression of gammadelta TCR (deltaTCR1+, deltaV1+, deltaV2-, deltaV3-, betaF1-) [10].
  • The RNA-binding protein TIA-1 (T-cell intracellular antigen 1) functions as a posttranscriptional regulator of gene expression and aggregates to form stress granules following cellular damage [11].
  • Further studies using RNA interference revealed that TIA-1 repressed the translation of bound mRNAs [11].
  • The interactions between TIA-1 and target transcripts were validated by IP of endogenous mRNAs, followed by reverse transcription and PCR-mediated detection, and by pulldown of biotinylated RNAs, followed by Western blotting [11].
  • TIA-1 and TIAR are RNA binding proteins of the RNA recognition motif (RRM)/ribonucleoprotein (RNP) family that have been implicated as effectors of apoptotic cell death [12].

Anatomical context of TIA1


Associations of TIA1 with chemical compounds

  • Recruitment of U1 to a class of weak 5' ss is promoted by binding of the protein TIA-1 to uridine-rich sequences immediately downstream from the 5' ss [15].
  • Furthermore, Percoll gradient fractionation of a cytolytic T cell clone (T4T8C1) showed the majority of TIA-1 to be contained in a low density membrane fraction that also contained serine protease activity [14].
  • Immunostaining of formalin-fixed tissues was used to determine in the intraepithelial compartment (1) the number of TIA1-expressing cells per 100 epithelial cells, (2) the number of IELs per 100 epithelial cells, (3) the ratio of TIA1-expressing IELs (TIA1/IEL ratio) [16].
  • Although RRM 3 (of either TIA-1 or TIAR) does not interact with the uridylate-rich sequences selected by the full-length proteins, it is a bona fide RNA binding domain capable of affinity-precipitating a population of cellular RNAs ranging in size from 0.5 to 5 kilobases [17].
  • Fas-activated serine/threonine kinase (FAST K) is known to interact with and phosphorylate TIA-1 [18].

Physical interactions of TIA1

  • The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5' splice sites [15].
  • Stress-induced depletion of eIF2-GTP-tRNA(i)(Met) allows the related RNA-binding proteins TIA-1 and TIAR to promote the assembly of eIF2-eIF5-deficient preinitiation complexes, the core constituents of SGs [19].

Regulatory relationships of TIA1

  • Nearly all CD8-positive cells expressed cytotoxic granules (TIA1), possibly causing the basal destruction [20].
  • These findings support the hypothesis that TNF-alpha-induced TIA-1 overexpression might sensitize endothelial cells to proapoptotic stimuli present in the tumor microenvironment and enhance NK cell cytotoxic activity against cancer cells [3].
  • Using in vitro splicing assays, we have shown that TIA-1 is directly involved in activating the 5' splice sites of the TIAR alternative exons [21].
  • Granzyme B (GrB) and T-cell-restricted intracellular antigen (TIA-1) are cytotoxic proteins that are specifically expressed by cytotoxic CD4 or CD8 positive T cells and natural killer cells [22].
  • All T- and NK/T-cell lymphomas strongly expressed TIA-1 and 63% expressed CD2 [23].
  • This suggests a potentially novel, dual role for TIA-1 in shuttling between DNA and RNA ligands to co-regulate COL2A1 expression at the level of transcription and pre-mRNA alternative splicing [24].

Other interactions of TIA1

  • Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1 [1].
  • These data indicate that, in CFTR exon 9, TIA-1 binding to the PCE recruits U1 small nuclear ribonucleoprotein to the weak 5'-ss and induces exon inclusion [25].
  • Molecular characterization of murine TIA-1 and TIAR RNA binding proteins provides the basis for a genetic analysis of the functional roles of these proteins during mammalian development [12].
  • The TIA-1 motif was found in the TNF-alpha and COX-2 mRNAs and in 3,019 additional UniGene transcripts (approximately 3% of the UniGene database), localizing preferentially to the 3' untranslated region [11].
  • The results argue that binding of TIA-1 in the vicinity of a 5' ss helps to stabilize U1 snRNP recruitment, at least in part, via a direct interaction with U1-C, thus providing one molecular mechanism for the function of this splicing regulator [15].

Analytical, diagnostic and therapeutic context of TIA1

  • Here, immunoprecipitation (IP) of TIA-1-RNA complexes, followed by microarray-based identification and computational analysis of bound transcripts, was used to elucidate a common motif present among TIA-1 target mRNAs [11].
  • In response to Fas ligation, it is rapidly dephosphorylated and concomitantly activated to phosphorylate TIA-1, a nuclear RNA-binding protein that has been implicated as an effector of apoptosis [26].
  • Here we describe a molecular dissection of the activities of TIA-1 [15].
  • We recently reported the molecular cloning of a cytotoxic granule-associated RNA-binding protein designated TIA-1 [13].
  • Although immunoblotting analysis of post-nuclear supernatants revealed TIA-1 protein to be restricted to CTLs, PCR analysis revealed the expression of TIA-1 and TIAR mRNA transcripts in a wide variety of cell types [13].


  1. Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. Dixon, D.A., Balch, G.C., Kedersha, N., Anderson, P., Zimmerman, G.A., Beauchamp, R.D., Prescott, S.M. J. Exp. Med. (2003) [Pubmed]
  2. Herpes simplex virus 1 induces cytoplasmic accumulation of TIA-1/TIAR and both synthesis and cytoplasmic accumulation of tristetraprolin, two cellular proteins that bind and destabilize AU-rich RNAs. Esclatine, A., Taddeo, B., Roizman, B. J. Virol. (2004) [Pubmed]
  3. Increased TIA-1 gene expression in the tumor microenvironment after locoregional administration of tumor necrosis factor-alpha to patients with soft tissue limb sarcoma. Mocellin, S., Provenzano, M., Lise, M., Nitti, D., Rossi, C.R. Int. J. Cancer (2003) [Pubmed]
  4. An immunohistochemical study of CD4, CD8, TIA-1 and CD56 subsets in inflammatory skin disease. Harvell, J.D., Nowfar-Rad, M., Sundram, U. J. Cutan. Pathol. (2003) [Pubmed]
  5. A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells. Tian, Q., Streuli, M., Saito, H., Schlossman, S.F., Anderson, P. Cell (1991) [Pubmed]
  6. On Again, off Again: The SRC-3 Transcriptional Coactivator Moonlights as a Translational Corepressor. Anderson, P., Kedersha, N. Mol. Cell (2007) [Pubmed]
  7. Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition. Izquierdo, J.M., Majós, N., Bonnal, S., Martínez, C., Castelo, R., Guigó, R., Bilbao, D., Valcárcel, J. Mol. Cell (2005) [Pubmed]
  8. TIA1 and mast cell tryptase in food allergy of children: increase of intraepithelial lymphocytes expressing TIA1 associates with allergy. Augustin, M., Karttunen, T.J., Kokkonen, J. J. Pediatr. Gastroenterol. Nutr. (2001) [Pubmed]
  9. Practice variability in management of transient ischemic attacks. Johnston, S.C., Smith, W.S. Eur. Neurol. (1999) [Pubmed]
  10. Variation in the histological pattern of nodal involvement by gamma/delta T-cell lymphoma. Charton-Bain, M.C., Brousset, P., Bouabdallah, R., Gaulard, P., Merlio, J.P., Dubus, P., Rostaing, L., de Roux, C., Weiller, P.J., Hassoun, J., Xerri, L. Histopathology (2000) [Pubmed]
  11. Identification and functional outcome of mRNAs associated with RNA-binding protein TIA-1. López de Silanes, I., Galbán, S., Martindale, J.L., Yang, X., Mazan-Mamczarz, K., Indig, F.E., Falco, G., Zhan, M., Gorospe, M. Mol. Cell. Biol. (2005) [Pubmed]
  12. Structure, tissue distribution and genomic organization of the murine RRM-type RNA binding proteins TIA-1 and TIAR. Beck, A.R., Medley, Q.G., O'Brien, S., Anderson, P., Streuli, M. Nucleic Acids Res. (1996) [Pubmed]
  13. Identification and functional characterization of a TIA-1-related nucleolysin. Kawakami, A., Tian, Q., Duan, X., Streuli, M., Schlossman, S.F., Anderson, P. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  14. A monoclonal antibody reactive with a 15-kDa cytoplasmic granule-associated protein defines a subpopulation of CD8+ T lymphocytes. Anderson, P., Nagler-Anderson, C., O'Brien, C., Levine, H., Watkins, S., Slayter, H.S., Blue, M.L., Schlossman, S.F. J. Immunol. (1990) [Pubmed]
  15. The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5' splice sites. Förch, P., Puig, O., Martínez, C., Séraphin, B., Valcárcel, J. EMBO J. (2002) [Pubmed]
  16. Increased TIA1-expressing intraepithelial lymphocytes in cow's milk protein intolerance. Hankard, G.F., Matarazzo, P., Duong, J.P., Mougenot, J.F., Navarro, J., Cézard, J.P., Peuchmaur, M. J. Pediatr. Gastroenterol. Nutr. (1997) [Pubmed]
  17. Individual RNA recognition motifs of TIA-1 and TIAR have different RNA binding specificities. Dember, L.M., Kim, N.D., Liu, K.Q., Anderson, P. J. Biol. Chem. (1996) [Pubmed]
  18. Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing. Izquierdo, J.M., Valcárcel, J. J. Biol. Chem. (2007) [Pubmed]
  19. Stressful initiations. Anderson, P., Kedersha, N. J. Cell. Sci. (2002) [Pubmed]
  20. Detection of expanded T cell clones in skin biopsy samples of patients with lichen sclerosus et atrophicus by T cell receptor-gamma polymerase chain reaction assays. Lukowsky, A., Muche, J.M., Sterry, W., Audring, H. J. Invest. Dermatol. (2000) [Pubmed]
  21. TIA-1 and TIAR activate splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on their own pre-mRNAs. Le Guiner, C., Lejeune, F., Galiana, D., Kister, L., Breathnach, R., Stévenin, J., Del Gatto-Konczak, F. J. Biol. Chem. (2001) [Pubmed]
  22. Expression of cytotoxic proteins by neoplastic T cells in mycosis fungoides increases with progression from plaque stage to tumor stage disease. Vermeer, M.H., Geelen, F.A., Kummer, J.A., Meijer, C.J., Willemze, R. Am. J. Pathol. (1999) [Pubmed]
  23. Nasal and nasal-type natural killer (NK)/T-cell lymphoma: immunophenotype and Epstein-Barr virus (EBV) association. Peh, S.C., Quen, Q.W. Med. J. Malaysia (2003) [Pubmed]
  24. Nuclear protein TIA-1 regulates COL2A1 alternative splicing and interacts with precursor mRNA and genomic DNA. McAlinden, A., Liang, L., Mukudai, Y., Imamura, T., Sandell, L.J. J. Biol. Chem. (2007) [Pubmed]
  25. An intronic polypyrimidine-rich element downstream of the donor site modulates cystic fibrosis transmembrane conductance regulator exon 9 alternative splicing. Zuccato, E., Buratti, E., Stuani, C., Baralle, F.E., Pagani, F. J. Biol. Chem. (2004) [Pubmed]
  26. Fas-activated serine/threonine kinase (FAST) phosphorylates TIA-1 during Fas-mediated apoptosis. Tian, Q., Taupin, J., Elledge, S., Robertson, M., Anderson, P. J. Exp. Med. (1995) [Pubmed]
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