Figure 7
Figure 7. Posttranslational regulation of p53 and regulation of p53-effectors. (A) Regulation of p53 transcriptional activities and stability. Under stress conditions, p53 protein is stabilized and activated. Various proteins (mostly shown on the left) and posttranslational modifications (mostly shown on the right) regulate p53 degradation and p53 TAs. Generally, acetylation (eg, by p300, CBP) and phosphorylation (eg, by CK2, Chk2) inhibit ubiquitination, stabilize and enhance p53 activity, whereas neddylation (eg, by FBXO11, NEDD) increases p53 stability but suppresses p53 function. However, association with p300 is required for MDM2-mediated polyubiquitination and degradation of p53. Methylation on different residues has different effects on p53. The methyltransferase SETD7 increases p53 stability; SETD8 inhibits p53 activity. Controversially, Setd7 is dispensable for the p53 function (cell-cycle arrest or apoptosis) in vivo. Effect of sumoylation is also controversial. Acetylation state of SUMO-1 affects its activity toward p53 stability. Ubiquitination decreases p53 stability and activity. MDM2 mediates p53 degradation and inhibits p53 acetylation and activity. NUB1 decreases neddylation by NEDD8 and stimulates p53 ubiquitination, promotes cytoplasmic localization of p53, and inhibits p53 TA. The atypical ubiquitin ligase E4F1 has no effect on p53 degradation or localization but modifies p53 transcriptional program by enhancing cell-cycle arrest and not apoptosis. In the diagram, solid green arrows indicate positive regulation; solid red lines, negative regulation; and hyphenated green arrows, up-regulation of gene expression. (B) Downstream dysregulation of the TP53 pathway by p53-independent pathways, including the PI3K/Akt and NF-κB pathways. The PI3K/Akt pathway counters both the p53-mediated extrinsic (designated as 1: by inhibiting Fas/CD95 death-inducing signaling complex activation without affecting Fas expression) and intrinsic (designated as 2: by increasing antiapoptotic gene expression and decreasing PUMA expression; designated as 4: by suppressing the metabolic up-regulation of PUMA, decreasing PUMA stability, and inhibiting BIM cytotoxicity) apoptotic pathways, and activates the NF-κB pro-survival function (designated as 3: by phosphorylation of NF-κB inhibitor IκBα). DISC indicates death-inducing signaling complex.

Posttranslational regulation of p53 and regulation of p53-effectors. (A) Regulation of p53 transcriptional activities and stability. Under stress conditions, p53 protein is stabilized and activated. Various proteins (mostly shown on the left) and posttranslational modifications (mostly shown on the right) regulate p53 degradation and p53 TAs. Generally, acetylation (eg, by p300, CBP) and phosphorylation (eg, by CK2, Chk2) inhibit ubiquitination, stabilize and enhance p53 activity, whereas neddylation (eg, by FBXO11, NEDD) increases p53 stability but suppresses p53 function. However, association with p300 is required for MDM2-mediated polyubiquitination and degradation of p53. Methylation on different residues has different effects on p53. The methyltransferase SETD7 increases p53 stability; SETD8 inhibits p53 activity. Controversially, Setd7 is dispensable for the p53 function (cell-cycle arrest or apoptosis) in vivo. Effect of sumoylation is also controversial. Acetylation state of SUMO-1 affects its activity toward p53 stability. Ubiquitination decreases p53 stability and activity. MDM2 mediates p53 degradation and inhibits p53 acetylation and activity. NUB1 decreases neddylation by NEDD8 and stimulates p53 ubiquitination, promotes cytoplasmic localization of p53, and inhibits p53 TA. The atypical ubiquitin ligase E4F1 has no effect on p53 degradation or localization but modifies p53 transcriptional program by enhancing cell-cycle arrest and not apoptosis. In the diagram, solid green arrows indicate positive regulation; solid red lines, negative regulation; and hyphenated green arrows, up-regulation of gene expression. (B) Downstream dysregulation of the TP53 pathway by p53-independent pathways, including the PI3K/Akt and NF-κB pathways. The PI3K/Akt pathway counters both the p53-mediated extrinsic (designated as 1: by inhibiting Fas/CD95 death-inducing signaling complex activation without affecting Fas expression) and intrinsic (designated as 2: by increasing antiapoptotic gene expression and decreasing PUMA expression; designated as 4: by suppressing the metabolic up-regulation of PUMA, decreasing PUMA stability, and inhibiting BIM cytotoxicity) apoptotic pathways, and activates the NF-κB pro-survival function (designated as 3: by phosphorylation of NF-κB inhibitor IκBα). DISC indicates death-inducing signaling complex.

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