T-cell intracellular antigens function as tumor suppressor genes
C Sánchez-Jiménez1, M D Ludeña2, J M Izquierdo1
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (CSIC/UAM), C/ Nicolás Cabrera 1, Madrid, Spain.
Abstract:
Knockdown of T-cell intracellular antigens TIA1 and TIAR in transformed cells triggers cell proliferation and tumor growth. Using a tetracycline-inducible system, we report here that an increased expression of TIA1 or TIAR in 293 cells results in reduced rates of cell proliferation. Ectopic expression of these proteins abolish endogenous TIA1 and TIAR levels via the regulation of splicing of their pre-mRNAs, and partially represses global translation in a phospho-eukaryotic initiation factor 2 alpha-dependent manner. This is accompanied by cell cycle arrest at G1/S and cell death through caspase-dependent apoptosis and autophagy. Genome-wide profiling illustrates a selective upregulation of p53 signaling pathway-related genes. Nude mice injected with doxycycline-inducible cells expressing TIA1 or TIAR retard, or even inhibit, growth of xenotumors. Remarkably, low expressions of TIA1 and TIAR correlate with poor prognosis in patients with lung squamous cell carcinoma. These findings strongly support the concept that TIA proteins act as tumor suppressor genes.
Insights
T-cell intracellular antigen (TIA) proteins TIA1 and TIAR act as tumor suppressors. Increased expression of TIA1 or TIAR inhibits cell proliferation and xenotumor growth, suggesting their therapeutic potential.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Knockdown of T-cell intracellular antigens TIA1 and TIAR promotes tumor growth.
- The precise role of TIA1 and TIAR in cancer development requires further elucidation.
Purpose of the Study:
- To investigate the function of TIA1 and TIAR in cell proliferation and tumor growth.
- To explore the underlying molecular mechanisms of TIA protein-mediated tumor suppression.
Main Methods:
- Utilized a tetracycline-inducible system for controlled expression of TIA1 and TIAR in 293 cells.
- Performed genome-wide profiling to analyze gene expression changes.
- Assessed cell proliferation, cell cycle, apoptosis, and autophagy.
- Evaluated xenotumor growth in nude mice models.
- Correlated TIA1 and TIAR expression with patient prognosis in lung squamous cell carcinoma.
Main Results:
- Increased TIA1 or TIAR expression reduced cell proliferation and induced G1/S cell cycle arrest.
- Ectopic TIA expression led to apoptosis and autophagy, and repressed global translation via phospho-eukaryotic initiation factor 2 alpha.
- Genome-wide profiling revealed upregulation of p53 signaling pathway genes.
- TIA1/TIAR expression inhibited xenotumor growth in vivo.
- Low TIA1/TIAR expression correlated with poor prognosis in lung cancer patients.
Conclusions:
- TIA proteins function as tumor suppressors by inhibiting cell proliferation and promoting cell death.
- TIA proteins regulate splicing, translation, and p53 signaling pathways.
- TIA1 and TIAR represent potential therapeutic targets for cancer treatment.
Related Concept Videos
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
02:23Abnormal Proliferation