p21WAF1 is component of a positive feedback loop that maintains the p53 transcriptional program

Pang, L. Y., Scott, M. , Hayward, R. L., Mohammed, H., Whitelaw, C. B. A., Smith, G. C.M. and Hupp, T. R. (2011) p21WAF1 is component of a positive feedback loop that maintains the p53 transcriptional program. Cell Cycle, 10(6), pp. 932-950. (doi: 10.4161/cc.10.6.15012) (PMID:21368573)

Abstract

The regulation of p53 activity through the MDM2 negative feedback loop is driven in part by an extrinsic ATM-pulse that maintains p53 oscillations in response to DNA damage. We report here that the p53 pathway has evolved an intrinsic positive feedback loop that is maintained by the p53-inducible gene product p21WAF1. p21-null cancer cells have defects in p53 protein turnover, reductions in MDM2-mediated degradation of p53, and reduced DNA damage-induced ubiquitination of p53. TLR3-IRF1 or ATM-dependent signaling to p53 is defective in p21-null cells and complementation of the p21 gene in p21-null cancer cells restores the p53 transcriptional response. The mechanism of p53 inactivity in p21-null cells is linked to a p53 protein equilibrium shift from chromatin into cytosolic fractions and complementation of the p21 gene into p21-null cells restores the nuclear localization of p53. A loss of p53 transcriptional function in murine B-cells heterozygous or homozygous null for p21 highlights a p21-gene dosage effect that maintains the full p53 transcriptional response. ATM inhibition results in nuclear exclusion of p53 highlighting a positive genetic interaction between ATM and p21. P21 protein oscillates in undamaged proliferating cells, and reductions of p21 protein using siRNA eliminate the DNA damage-induced p53 pulse. The p53 transcription program has evolved a negative feedback loop maintained by MDM2 that is counteracted by a positive feedback loop maintained by ATM-p21 the balance of which controls the specific activity of p53 as a transcription factor.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Scott, Dr Mary
• Authors: Pang, L. Y., Scott, M., Hayward, R. L., Mohammed, H., Whitelaw, C. B. A., Smith, G. C.M., and Hupp, T. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Cycle
• Publisher: Taylor & Francis
• ISSN: 1538-4101
• ISSN (Online): 1551-4005
• Published Online: 15 March 2011