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The Ras Gene

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Abnormal Proliferation

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Replicative Cell Senescence

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The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...

Cancer-Critical Genes I: Proto-oncogenes

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Related Experiment Video

Updated: Jul 8, 2026

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

Published on: August 12, 2018

PPP1CA contributes to the senescence program induced by oncogenic Ras.

Maria E Castro¹, Irene Ferrer, Alberto Cascón

¹Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.

|January 22, 2008

Summary

Oncogenic Ras and p53 induce senescence. Protein phosphatase 1-alpha (PPP1CA) loss bypasses this arrest by affecting ceramide levels and pRb dephosphorylation, suggesting a role in tumor suppression.

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Induction and Validation of Cellular Senescence in Primary Human Cells

Induction and Validation of Cellular Senescence in Primary Human Cells

Published on: June 20, 2018

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Last Updated: Jul 8, 2026

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

Published on: August 12, 2018

Induction and Validation of Cellular Senescence in Primary Human Cells

Induction and Validation of Cellular Senescence in Primary Human Cells

Published on: June 20, 2018

Area of Science:

Cellular senescence
Tumor suppressor pathways
Oncogene-induced signaling

Background:

Conditional murine p53 (p53val135) and oncogenic Ras induce a senescent-like growth arrest.
Identifying key regulators of Ras/p53-induced senescence is crucial for understanding tumor suppression.

Purpose of the Study:

To identify novel regulators involved in Ras/p53-induced senescence.
To elucidate the role of Protein Phosphatase 1-alpha catalytic subunit (PPP1CA) in this process.

Main Methods:

Retroviral-based genetic screening to identify genes involved in senescence bypass.
Short hairpin RNA (shRNA) mediated knockdown of PPP1CA.
Analysis of p53-dependent p21 induction and pRb dephosphorylation.
Ceramide level measurements and functional assays.
Analysis of PPP1CA gene status in human carcinomas.

Main Results:

Loss of PPP1CA function bypasses Ras/p53-induced growth arrest and senescence.
PPP1CA knockdown impairs p53-dependent p21 induction and pRb dephosphorylation.
Oncogenic Ras increases intracellular ceramide and PPP1CA protein levels.
Ceramide addition induces senescence, which is blocked by PPP1CA downregulation.
PPP1CA allele loss is observed in kidney and colorectal carcinomas; altered splice variants impact tumor growth.

Conclusions:

Oncogenic stress via Ras leads to ceramide accumulation, enhancing PPP1CA activity.
Increased PPP1CA activity promotes pRb dephosphorylation and initiates p53-induced arrest, contributing to tumor suppression.
PPP1CA is a critical mediator in the Ras/p53 senescence pathway and a potential tumor suppressor in carcinomas.