02966nas a2200409 4500008004100000245008000041210006900121260001600190300001400206490000800220520168500228653001201913653001801925653001401943653003301957653001501990653003102005653000902036653001902045653001702064653002802081653001302109653001402122653003002136653002302166653003302189100002102222700001402243700002402257700002202281700002302303700002002326700001802346700002202364700002102386856014902407 2011 eng d00aMitochondrial dysfunction impairs tumor suppressor p53 expression/function.0 aMitochondrial dysfunction impairs tumor suppressor p53 expressio c2011 Jun 10 a20297-3120 v2863 a
Recently, mitochondria have been suggested to act in tumor suppression. However, the underlying mechanisms by which mitochondria suppress tumorigenesis are far from being clear. In this study, we have investigated the link between mitochondrial dysfunction and the tumor suppressor protein p53 using a set of respiration-deficient (Res(-)) mammalian cell mutants with impaired assembly of the oxidative phosphorylation machinery. Our data suggest that normal mitochondrial function is required for γ-irradiation (γIR)-induced cell death, which is mainly a p53-dependent process. The Res(-) cells are protected against γIR-induced cell death due to impaired p53 expression/function. We find that the loss of complex I biogenesis in the absence of the MWFE subunit reduces the steady-state level of the p53 protein, although there is no effect on the p53 protein level in the absence of the ESSS subunit that is also essential for complex I assembly. The p53 protein level was also reduced to undetectable levels in Res(-) cells with severely impaired mitochondrial protein synthesis. This suggests that p53 protein expression is differentially regulated depending upon the type of electron transport chain/respiratory chain deficiency. Moreover, irrespective of the differences in the p53 protein expression profile, γIR-induced p53 activity is compromised in all Res(-) cells. Using two different conditional systems for complex I assembly, we also show that the effect of mitochondrial dysfunction on p53 expression/function is a reversible phenomenon. We believe that these findings will have major implications in the understanding of cancer development and therapy.
10aAnimals10aBase Sequence10aCell Line10aElectron Transport Complex I10aGamma Rays10aGene Expression Regulation10aMice10aMice, Knockout10aMitochondria10aMolecular Sequence Data10aMutation10aNeoplasms10aOxidative Phosphorylation10aOxygen Consumption10aTumor Suppressor Protein p531 aCompton, Shannon1 aKim, Chul1 aGriner, Nicholas, B1 aPotluri, Prasanth1 aScheffler, Immo, E1 aSen, Sabyasachi1 aJerry, Joseph1 aSchneider, Sallie1 aYadava, Nagendra uhttps://www.umass.edu/veterinary-animal-sciences/research-faculty/publications/mitochondrial-dysfunction-impairs-tumor-suppressor-p53-expression