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

p19ARF has been implicated as a key regulator of p53 stability and activati on. While numerous stresses activate the p53 growth arrest pathway, those r equiring p19ARF remain to be elucidated. We used p19ARF knockout mouse embr yo fibroblasts to show that DMA damage and microtubule disruption require p 19ARF to induce p53 responses, whereas ribonucleotide depletion and inhibit ion of RNA synthesis by low doses of actinomycin D do not. The data provide evidence that the arrest pathway activated by ribonucleotide depletion inv olves some different signal transducers than those activated by DNA damage or microtubule disruption. We also present biochemical analyses that provid e insights into the mechanism by which p53 and p19ARF cooperate in normal c ells to induce cell cycle arrest.