p21^WAF1is component of a positive feedback loop that maintains the p53 transcriptional program

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

“…It has been widely observed that deletion of CDKN1A (encodes p21) in HCT116 cells leads to increased stabilization and accumulation of p53 (39,40). We confirmed this increase of p53 protein in p21 Ϫ/Ϫ cells compared with HCT116 cells (Fig.…”

Grail as a molecular determinant for the functions of the tumor suppressor p53 in tumorigenesis

“…Paradoxically, p21 might also promote apoptosis through both p53-dependent and p53-independent mechanisms under certain cellular stresses. 22,23 The present study identified a p53-interacting glycoprotein, Grail, using the yeast SOS recruitment system, 24 and demonstrated that Grail (in addition to Mdm2) is a target for p53, and physically and functionally interacts with the N-terminus of p53 to decrease its protein stability and transactivation activity. In addition, we found that Grail has a role in cell cycle arrest and apoptosis in a p53-dependent manner following treatment with DNA-damaging agents.…”

MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program

“…9 In addition, MDM2 nuclear entry is inhibited via induction of p53-responsive PTEN, 10 and p53-inducible p21 maintains another positive feedback loop. 11 A fifth possible factor is oscillation of the p53-MDM2 autoregulatory feedback loop ( Figure 1C), which has not been recognized by the previous prognostic studies. Elegant models and laboratory observations have shown that cellular levels of WT-p53 and MDM2 fluctuate in an oscillatory fashion in response to stress, such as DNA damage, hypoxia, or oncogene activation, and that the numbers of pulses and the fraction of cells with oscillatory pulses increase with the strength of DNA damage.…”

“…Elegant models and laboratory observations have shown that cellular levels of WT-p53 and MDM2 fluctuate in an oscillatory fashion in response to stress, such as DNA damage, hypoxia, or oncogene activation, and that the numbers of pulses and the fraction of cells with oscillatory pulses increase with the strength of DNA damage. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The oscillatory kinetics and the variable amplitude of p53/MDM2 pulses over cell population may affect the measurement of MDM2 expression using immunohistochemistry (IHC), a commonly used method in clinical diagnostic and prognostic studies. If the study cohort is too small, or the cutoff is inappropriately established, the survival difference between 2 groups may not be truly reflected.…”