How Does P53 Affect The Mitochondria-mediated Apoptosis?

How Does P53 Affect The Mitochondria-mediated Apoptosis?

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In addition to my last post, I have to talk about transcriptional function of p53 further. As we mentioned, based on its effect of tumor suppression, activation or reactivation of p53 has been recognised as one potent therapy for cancer, and several drugs targeting p53 have been on clinical tests. This activity of p53 largely depends on its ability of inducing apoptosis through the mitochondria-mediated pathway.

Genotoxic stress primarily activates the intrinsic pathway, but only a minor extrinsic pathway. The permeability of mitochondria outer membrane plays a central role in the intrinsic pathway. Mitochondrial outer membrane permeabilisation (MOMP) releases the signaling molecules between the outer and inner mitochondrial membranes into the cytosol, which induces caspase activation and other processes. MOMP is the key event for initiating the intrinsic pathway, and it is regulated by the relative abundance, posttranslational modifications and conformation of Bcl-2 family anti-apoptotic members, who could maintain membrane integrity, and pro-apoptotic members, who could induce membrane permeabilisation. Bcl-2 inhibitor. It has been demonstrated that the induction of mitochondria-mediated apoptosis requires the activation of either pro-apoptotic member of the Bcl-2 protein family, Bax or Bak. They are essential for forming pores in the mitochondrial membrane. Nutlin-3.



How does p53 affect the mitochondria-mediated apoptosis? As a transcription factor, p53 could not only induce pro-apoptotic Bcl-2 members, such as Puma, Bax, Bid and Noxa, but also suppress the transcription of anti-apoptotic genes, such as those encoding survivin, Bcl-2 and Bcl-xL. ABT-263. But no single gene could explain p53s full apoptotic capacity. In addition to these activities, p53 could induce an alternative route to death, apoptosis independently of its transcriptional function. The hallmark of these pathways is that p53 is accumulated by stress in the cytosol or mitochondria where non-nuclear p53 leads to direct activation of Bak and/or Bax. ABT-737. The involvement of transcription-independent apoptosis in the complex apoptosis process is based on the fact that stress could induce p53-dependent apoptosis when its transcriptional activity was inhibited, and that p53 could induce MOMP and cytochrome c release rapidly from mitochondria in vitro.

Several studies about the interactions of p53 with Bcl-2 proteins revealed that stress-induced p53 can bind to Bak, release it from an inhibitory complex with Mcl-1, leading to oligomerisation and activation of Bak. For Bax, p53 can directly promote its activation. Pomalidomide. With the help of Puma, the initial complexity of stress-induced p53-Bcl-xL is disrupted, and sufficient amounts of active p53 are released to promote apoptosis. In another way, p53 can bind to Ku70, a DNA repair protein, disrupt the interaction of Bax-Ku70, and result in Bax activation and apoptosis. In addition to the interactions with Bax and Bak, p53 is able to interact with another pro-apoptotic Bcl-2 family member Bad.

What is the relevance between transcription-independent and transcription-dependent p53 activities? Well discuss this problem later.

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