Depletion of T-cell intracellular antigen (TIA)-proteins promotes cell proliferation

Background: TIA-1 (T-cell intracellular antigen-1) and TIAR/TIAL1 (TIA-1 related/like protein) are two DNA/RNA binding proteins broadly expressed in eukaryotic cells, which participate in the regulation of gene expression through RNA metabolism. Despite the biological relevance of these regulators there are no genome-wide studies assessing the global transcriptomic and phenotypic impacts upon expression and/or function changes of these proteins. Results: Using high-throughput gene expression profiling, we found that the TIA-1/TIAR-depleted cell phenotype is linked to a transcriptome involved in the control of inflammation, cell-cell signalling, immune-suppression, angiogenesis, metabolism and cell proliferation. Induced genes included pro-inflammatory cytokines, inflammatory chemokines, growth-stimulating factors and pro-angiogenic inducers. Repressed genes involved the RAS oncogene family member RAB40B, regulators of cytoskeleton organization and biogenesis and a mitochondrial modulator. Consistent with these observations, depletion of TIA-proteins in HeLa cells results in increased cell proliferation, altered cell-cycle and anchorage-independent growth. Mechanistically, the changes associated to the steady-state target mRNA levels regulated by TIA-proteins are consistent with overlapping effects on gene basal transcription rate and mRNA turnover. Conclusions: Collectively, our findings suggest a role for TIA-proteins as cellular sensors, which modulate gene expression control at transcriptional and pos-transcriptional levels coupling cell proliferation responses and metabolic homeostasis to cell survival and growth.