Disease relevance of TIA1

• Colon cancer cells demonstrated to overexpress COX-2 through increased polysome association with COX-2 mRNA also showed defective TIA-1 binding both in vitro and in vivo [1].
• 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 [2].
• Increased TIA-1 gene expression in the tumor microenvironment after locoregional administration of tumor necrosis factor-alpha to patients with soft tissue limb sarcoma [3].
• Given that CD8, TIA-1, and CD56 are linked to aggressive lymphoproliferative disorders (i.e. subcutaneous panniculitic T-cell lymphoma, natural killer (NK), and NK/T-cell lymphomas), it would be important to determine their specificity for cutaneous hematologic malignancies [4].
• CONCLUSION: TIA-1- and CD56-positive lymphocytes are common participants in routine inflammatory dermatoses, and therefore these markers are not specific for aggressive lymphoproliferative disorders [4].

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

• TIA1 and mast cell tryptase in food allergy of children: increase of intraepithelial lymphocytes expressing TIA1 associates with allergy [8].
• There was more agreement in the second case, a posterior circulation TIA 1 day prior with atrial fibrillation, in which 84% chose hospital admission, 74% chose intravenous heparin and 90% treated with some form of anticoagulation [9].

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

• The ability of recombinant TIA-1 to induce DNA fragmentation in permeabilized cells suggested that this protein is the granule component responsible for inducing apoptosis in cytolytic lymphocyte (CTL) targets [13].
• TIA-1 reacted strongly with NK cell clones and CD8+ cytolytic T cell clones, and less strongly with CD4+-activated T cell clones, suggesting a preferential expression in cells possessing cytolytic potential [14].
• TIA-1 did not react with any of a panel of T cell lines, B cell lines, or monocytoid cell lines [14].
• Immunoelectron microscopy showed TIA-1 to decorate the membranes of electron lucent and electron dense cytoplasmic granules in this same cytolytic T cell clone [14].
• In vitro, TIA-1 was expressed by endothelial cells, fibroblasts, CTLs and NK cells [3].

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].

References