TL;DR: A novel gene named PUMA (p53 upregulated modulator of apoptosis) is identified as a target for activation by p53, and PUMA is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1-dependent pathway.
TL;DR: In mice with either noxa or puma disrupted, decreased DNA damage–induced apoptosis in fibroblasts is observed, although only loss of Puma protected lymphocytes from cell death, and Puma deficiency protected cells against diverse p53-independent cytotoxic insults.
Abstract: Apoptosis provoked by DNA damage requires the p53 tumor suppressor, but which of the many p53-regulated genes are required has remained unknown. Two genes induced by this transcription factor, noxa and puma (bbc3), stand out, because they encode BH3-only proteins, proapoptotic members of the Bcl-2 family required to initiate apoptosis. In mice with either noxa or puma disrupted, we observed decreased DNA damage-induced apoptosis in fibroblasts, although only loss of Puma protected lymphocytes from cell death. Puma deficiency also protected cells against diverse p53-independent cytotoxic insults, including cytokine deprivation and exposure to glucocorticoids, the kinase inhibitor staurosporine, or phorbol ester. Hence, Puma and Noxa are critical mediators of the apoptotic responses induced by p53 and other agents.
TL;DR: Through global profiling of genes that were expressed soon after p53 expression, a novel gene termed PUMA (p53 upregulated modulator of apoptosis) was identified and it was found to be exclusively mitochondrial and to bind to Bcl-2 and Bcl(L) through a BH3 domain.
TL;DR: It is shown that the microRNA miR-34a regulates silent information regulator 1 (SIRT1) expression, which functions as a tumor suppressor, in part, through a SIRT1-p53 pathway.
Abstract: MicroRNA 34a (miR-34a) is a tumor suppressor gene, but how it regulates cell proliferation is not completely understood. We now show that the microRNA miR-34a regulates silent information regulator 1 (SIRT1) expression. MiR-34a inhibits SIRT1 expression through a miR-34a-binding site within the 3′ UTR of SIRT1. MiR-34 inhibition of SIRT1 leads to an increase in acetylated p53 and expression of p21 and PUMA, transcriptional targets of p53 that regulate the cell cycle and apoptosis, respectively. Furthermore, miR-34 suppression of SIRT1 ultimately leads to apoptosis in WT human colon cancer cells but not in human colon cancer cells lacking p53. Finally, miR-34a itself is a transcriptional target of p53, suggesting a positive feedback loop between p53 and miR-34a. Thus, miR-34a functions as a tumor suppressor, in part, through a SIRT1-p53 pathway.
TL;DR: It is reported that Puma is essential for hematopoietic cell death triggered by ionizing radiation, deregulated c-Myc expression, and cytokine withdrawal, and required for IR-induced death throughout the developing nervous system and accounts for nearly all of the apoptotic activity attributed to p53 under these conditions.