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Cellular senescence bypass screen identifies new putative tumor suppressor genes
J F M Leal1, J Fominaya, A Cascón
1Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
Abstract:
Senescence is a mechanism that limits cellular lifespan and constitutes a barrier against cellular immortalization. To identify new senescence regulatory genes that might play a role in tumorigenesis, we have designed and performed a large-scale antisense-based genetic screen in primary mouse embryo fibroblasts (MEFs). Out of this screen, we have identified five different genes through which loss of function partially bypasses senescence. These genes belong to very different biochemical families: csn2 (component of the Cop9 signalosome), aldose reductase (a metabolic enzyme) and brf1 (subunit of the RNA polymerase II complex), S-adenosyl homocysteine hydrolase and Bub1. Inactivation, at least partial, of these genes confers resistance to both p53- and p16INK4a-induced proliferation arrest. Furthermore, such inactivation inhibits p53 but not E2F1 transcriptional activity and impairs DNA-damage-induced transcription of p21. Since the aim of the screen was to identify new regulators of tumorigenesis, we have tested their inactivation in human tumors. We have found, either by northern blot or quantitative reverse transcriptase-PCR analysis, that the expression of three genes, Csn2, Aldose reductase and Brf1, is lost at different ratios in tumors of different origins. These genes are located at common positions of loss of heterogeneity (15q21.2, 7q35 and 14q32.33); therefore,we have measured genomic losses of these specific genes in different tumors. We have found that Csn2 and Brf1 also show genomic losses of one allele in different tumors. Our data suggest that the three genes identified in the genome-wide loss-of-function genetic screen are putative tumor suppressors located at 15q21.2; 7q35 and 14q32.33.
Insights
We identified five genes that bypass senescence when their function is lost, suggesting they regulate cell lifespan and tumor suppression. Three of these genes (Csn2, Aldose reductase, Brf1) show reduced expression or genomic loss in human tumors.
Area of Science:
- Cell Biology
- Genetics
- Oncology
Background:
- Cellular senescence limits lifespan and prevents uncontrolled proliferation, acting as a tumor suppressor mechanism.
- Identifying genes that regulate senescence is crucial for understanding tumorigenesis.
Purpose of the Study:
- To discover novel senescence regulatory genes involved in tumor suppression.
- To investigate the role of identified genes in human cancers.
Main Methods:
- A large-scale antisense-based genetic screen was performed in primary mouse embryo fibroblasts (MEFs).
- Gene expression and genomic losses were analyzed in human tumors using Northern blot and quantitative reverse transcriptase-PCR.
Main Results:
- Five genes (csn2, aldose reductase, brf1, S-adenosyl homocysteine hydrolase, Bub1) were identified, whose loss-of-function partially bypasses senescence.
- Inactivation of these genes conferred resistance to p53- and p16INK4a-induced proliferation arrest.
- Expression loss and genomic losses (including heterozygous deletions) of Csn2, Aldose reductase, and Brf1 were observed in various human tumors.
Conclusions:
- Csn2, Aldose reductase, and Brf1 function as putative tumor suppressors.
- These genes are located at chromosomal regions frequently altered in cancer (15q21.2, 7q35, and 14q32.33).
- The identified genes represent novel regulators of senescence and potential targets for cancer therapy.
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