Abstract
p53 is a major cellular tumor suppressor that in addition to its nuclear, transcription-dependent activity is also known to function extranuclearly. Cellular stressors such as reactive oxygen species can promote translocation of p53 into mitochondria where it acts to protect mitochondrial genome or trigger cell death via transcription-independent manner. Here we report that the mammalian homologue of yeast mitochondrial Afg1 ATPase (LACE1) promotes translocation of p53 into mitochondria. We further show that LACE1 exhibits significant pro-apoptotic activity, which is dependent on p53, and that the protein is required for normal mitochondrial respiratory function. LACE1 physically interacts with p53 and is necessary for mitomycin c-induced translocation of p53 into mitochondria. Conversely, increased expression of LACE1 partitions p53 to mitochondria, causes reduction in nuclear p53 content and induces apoptosis. Thus, LACE1 mediates mitochondrial translocation of p53 and its transcription-independent apoptosis.
Highlights
Tumor suppressor p53 represents a central molecule of a complex cellular stress signaling pathway [1, 2]
We further show that LACE1 exhibits significant pro-apoptotic activity, which is dependent on p53, and that the protein is required for normal mitochondrial respiratory function
By performing subcellular fractionation with subsequent immunoblot detection using anti-LACE1 antibody (Abcam), we found that the endogenous processed LACE1 (~50 kDa) is highly enriched in mitochondrial fractions of human embryonic kidney 293 (HEK293) cells (Figure 1A)
Summary
Tumor suppressor p53 represents a central molecule of a complex cellular stress signaling pathway [1, 2]. P53 mediates a wide range of cellular outcomes that might include cell cycle arrest, DNA repair, senescence, and programmed cell death [1]. LACE1 is a mammalian homologue of yeast Afg (ATPase family gene 1) mitochondrial ATPase, a member of SEC18-NSF, PAS1, CDC48-VCP, TBP family of ATPases [12]. It is an evolutionary well conserved protein that contains an ATP/GTP binding P-loop (Walker A motif) [13, 14]. We have examined cellular function of LACE1 protein and found that it interacts with p53 tumor suppressor and mediates its mitochondrial translocation and apoptosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
