Abstract
Although the p53 tumor suppressor/transcription factor often accumulates in the cytoplasm of healthy cells, limited information is available on the cytoplasmic function of p53. Here, we show that cytoplasmic p53 suppresses cell invasion by reducing mitochondrial reactive oxygen species (ROS) levels. Analysis revealed that this function is mediated by Bcl-2 family proteins: Cytoplasmic p53 binds Bcl-w, liberating Bax, which then binds ND5, a subunit of respiratory complex-I, thereby suppressing complex-I activity and thus ROS production. The G13289A mutation of ND5, identified in cancer patients, prevents Bax/ND5 interactions and promotes ROS production and cell invasion. We also showed that Bcl-XL and Bak can substitute for Bcl-w and Bax, respectively, regulating complex-I activity and supporting the cytoplasmic function of p53; nuclear p53 also suppresses complex-I activity by inducing Bax expression. Studies in animal models support the notion that p53 and Bcl-2 family proteins exhibit these functions in vivo. This study demonstrates a link between p53 and Bcl-2 proteins as regulators of ROS production and cellular invasiveness, and reveals complex-I, especially ND5, as their functional target.
Highlights
The p53 tumor suppressor regulates numerous cellular functions, promoting cell death and suppressing cell migration and invasion [1]
We showed that Bcl-XL and Bak can substitute for Bcl-w and Bax, respectively, regulating complex-I activity and supporting the cytoplasmic function of p53; nuclear p53 suppresses complex-I activity by inducing Bax expression
Similar results were obtained with p53K305N, suggesting nuclear and cytoplasmic p53 suppress cell invasion by blocking the reactive oxygen species (ROS)/phosphoinositide 3-kinase (PI3K)/Akt/ matrix metalloproteinase-2 (MMP-2) pathway
Summary
The p53 tumor suppressor regulates numerous cellular functions, promoting cell death and suppressing cell migration and invasion [1]. P53 wild-type and mutant derivatives frequently accumulate in the cytoplasm of normal and cancer cells [36], reflecting a non-transcriptional, cytoplasmic function in healthy cells. Information on this possibility is quite limited. The pro-survival subfamily includes Bcl-2, Bcl-XL, and Bcl-w, whereas the pro-apoptotic subfamily comprises the multidomain (Bax and Bak) and BH3-only (Bid and others) groups. Pro-survival members bind to multidomain pro-apoptotic members and inhibit their apoptotic activities. These interactions are disrupted by BH3-only members, which are activated upon apoptotic stimulation. Multidomain pro-apoptotic members attack the mitochondria, inducing apoptosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
