P53 upregulated modulator of apoptosis

The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death. The PUMA protein is part of the BH3-only subgroup of Bcl-2 family proteins. This group of proteins only share sequence similarity in the BH3 domain, which is required for interactions with Bcl-2-like proteins, such as Bcl-2 and Bcl-xL. Structural analysis has shown that PUMA directly binds to antiapoptotic Bcl-2 family proteins via an amphiphatic α-helical structure which is formed by the BH3 domain. The mitochondrial localization of PUMA is dictated by a hydrophobic domain on its C-terminal portion. PUMA protein degradation is regulated by phosphorylation at a conserved serine residue at position 10.[31] Biochemical studies have shown that PUMA interacts with antiapoptotic Bcl-2 family members such as Bcl-xL, Bcl-2, Mcl-1, Bcl-w, and A1, inhibiting their interaction with the proapoptotic molecules, Bax and Bak. When the inhibition of these is lifted, they result in the translocation of Bax and activation of mitochondrial dysfunction resulting in release of mitochondrial apoptogenic proteins cytochrome c, SMAC, and apoptosis-inducing factor (AIF) leading to caspase activation and cell death. Because PUMA has high affinity for binding to Bcl-2 family members, another hypothesis is that PUMA directly activates Bax and/or Bak and through Bax multimerization triggers mitochondrial translocation and with it induces apoptosis.