Transcriptome-wide analysis links the short-term expression of the b isoforms of TIA proteins to protective proteostasis-mediated cell quiescence response

Abstract

Control of gene expression depends on genetics and environmental factors. The T-cell intracellular antigens T-cell intracellular antigen 1 (TIA1), TIA1-like/related protein (TIAL1/TIAR) and human antigen R (HuR/ELAVL1) are RNA-binding proteins that play crucial roles in regulating gene expression in both situations. This study used massive sequencing analysis to uncover molecular and functional mechanisms resulting from the short-time expression of the b isoforms of TIA1 and TIAR, and of HuR in HEK293 cells. Our gene profiling analysis identified several hundred differentially expressed genes (DEGs) and tens of alternative splicing events associated with TIA1b, TIARb and HuR overexpression. Gene ontology analysis revealed that the controlled expression of these proteins strongly influences the patterns of DEGs and RNA variants preferentially associated with development, reproduction, cell cycle, metabolism, autophagy and apoptosis. Mechanistically, TIA1b and TIARb isoforms display both common and differential effects on the regulation of gene expression, involving systematic perturbations of cell biosynthetic machineries (splicing and translation). The transcriptome outputs were validated using functional assays of the targeted cellular processes as well as expression analysis for selected genes. Collectively, our observations suggest that early TIA1b and TIARb expression operates to connect the regulatory crossroads to protective proteostasis responses associated with a survival quiescence phenotype.

In silico identification of EP400 and TIA1 as critical transcription factors involved in human hepatocellular carcinoma relapse

“…TIA1 is a member of an RNA-binding protein family and possesses nucleolytic activity against cytotoxic lymphocyte target cells (68). In the present study, TIA1 was found to be associated with the RFS and DFS of patients with HCC.…”

The Multifunctional Faces of T-Cell Intracellular Antigen 1 in Health and Disease

“…Although not considered a cancer-driver protein, TIA1 does have a role in tumorigenesis via its capacity to transcriptionally/post-transcriptionally regulate genes belonging to key pathways for tumor development. In this context, TIA1 exerts a dual function, as it has been shown that depending on the processes regulated in different cancers, it can act both as a tumor suppressor and an oncogene [77][78][79][80]83,87,88,90,113,[172][173][174][175]. Contrastingly, TIA1 also controls processes that can prevent the development of tumors: it regulates the alternative splicing of Fas, an apoptosis receptor [37,38]; it is a translational repressor of TNFα and regulates the expression of cyclooxygenase 2 (COX2), both related to pro-inflammatory processes [41,132]; it regulates alternative splicing of the fibroblast growth-factor receptor (FGFR2) [13]; it affects the expression and can suppress signaling of HIF1α, involved in angiogenesis [65]; and it is involved in alternative splicing or post-transcriptional regulation of the tumor-suppressor genes neurofibromatosis type 1 (NF1), Wilms' tumor 1 (WT1) and programmed cell death 4 (PDCD4) [172][173][174][175].…”

“…In this context, TIA1 exerts a dual function, as it has been shown that depending on the processes regulated in different cancers, it can act both as a tumor suppressor and an oncogene [77][78][79][80]83,87,88,90,113,[172][173][174][175]. Contrastingly, TIA1 also controls processes that can prevent the development of tumors: it regulates the alternative splicing of Fas, an apoptosis receptor [37,38]; it is a translational repressor of TNFα and regulates the expression of cyclooxygenase 2 (COX2), both related to pro-inflammatory processes [41,132]; it regulates alternative splicing of the fibroblast growth-factor receptor (FGFR2) [13]; it affects the expression and can suppress signaling of HIF1α, involved in angiogenesis [65]; and it is involved in alternative splicing or post-transcriptional regulation of the tumor-suppressor genes neurofibromatosis type 1 (NF1), Wilms' tumor 1 (WT1) and programmed cell death 4 (PDCD4) [172][173][174][175]. In line with these observations and the role of TIA1 as a potential tumor suppressor, knockdown of TIA proteins in HeLa cells increases cell proliferation, tumor growth and invasion [31,89], while its overexpression leads to cell-cycle arrest, cell death and slow xenotumor development in mice [83].…”

T-Cell Intracellular Antigen 1-Like Protein in Physiology and Pathology

“…Ablation of TIAR in mouse embryonic fibroblasts stimulates high rates of adaptive autophagy [ 93 ]. Contrastingly, transcriptome-wide analysis links the short-term expression of TIARb to a protective proteostasis-mediated cell quiescence response [ 95 , 107 ].…”