Proceedings of the National Academy of Sciences of the United States of America

Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion.

PMID 10716710


p19ARF has been implicated as a key regulator of p53 stability and activation. While numerous stresses activate the p53 growth arrest pathway, those requiring p19ARF remain to be elucidated. We used p19ARF knockout mouse embryo fibroblasts to show that DNA damage and microtubule disruption require p19ARF to induce p53 responses, whereas ribonucleotide depletion and inhibition of RNA synthesis by low doses of actinomycin D do not. The data provide evidence that the arrest pathway activated by ribonucleotide depletion involves some different signal transducers than those activated by DNA damage or microtubule disruption. We also present biochemical analyses that provide insights into the mechanism by which p53 and p19ARF cooperate in normal cells to induce cell cycle arrest.