A novel p53‐inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis‐inducing factor (AIF)

Abstract

The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identi¢ed PRG3 (p53-responsive gene 3), which is induced speci¢cally under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. PRG3 has signi¢cant homology to bacterial oxidoreductases and the apoptosis-inducing factor, AIF, and the gene was assigned to chromosome 10q21.3^q22.1. Expression of PRG3 was induced by the activation of endogenous p53 and it contains a p53-responsive element. Unlike AIF, PRG3 localizes in the cytoplasm and its ectopic expression induces apoptosis. An amino-terminal deletion mutant of PRG3 that lacks a putative oxidoreductase activity retains its apoptotic activity, suggesting that the oxidoreductase activity is dispensable for the apoptotic function of PRG3. The PRG3 gene is thus a novel p53 target gene in a p53-dependent apoptosis pathway. ß

The p53-inducible apoptotic protein AMID is not required for normal development and tumor suppression

“…Similar to AIF, overexpression of AMID induces caspase-independent apoptosis (Ohiro et al, 2002;Wu et al, 2002). Expression of AMID is upregulated by p53 and genotoxins and downregulated in tumors in comparison to their matched normal tissues, pointing to the possibility that AMID is involved in p53-mediated apoptotic effect (Ohiro et al, 2002;Wu et al, 2004). In this study, we generated AMID gene knockout mice in an attempt to investigate the physiological and pathological roles of AMID in vivo.…”

“…Overexpression of AMID induces cell death with characteristic apoptotic morphology and this is independent of caspase activation (Ohiro et al, 2002;Wu et al, 2002). Furthermore, transcription of human AMID gene is induced by p53 and expression of AMID is significantly downregulated in some tumors in comparison to their matched normal tissues (Ohiro et al, 2002;Wu et al, 2004). These studies point to the possibility that AMID may be involved in p53-induced downstream effects such as growth arrest or apoptosis and might be a potential tumor suppressor gene.…”

“…Mouse AMID is induced by genotoxins Previously, it has been shown that human AMID mRNA is transcriptionally induced by p53 and genotoxins (Ohiro et al, 2002;Wu et al, 2002). We determined whether mouse AMID is also upregulated by genotoxins in MEFs.…”

“…Gene knockout studies suggest that AIF is required for apoptosis of embryonic stem cells induced by serum deprivation, and is essential for apoptosis during cavitation of embryonic bodies (Joza et al, 2001). We and others have identified an AIF-homologous flavoprotein called AMID/PRG3 (Ohiro et al, 2002;Wu et al, 2002). AMID lacks a mitochondrial localization sequence but shares significant homology with AIF and NADH-oxidoreductases from bacteria to mammalian species.…”

“…Immunofluorescent staining and biochemical experiments suggest that AMID is associated with the outer membrane of mitochondria. Overexpression of AMID induces cell death with characteristic apoptotic morphology and this is independent of caspase activation (Ohiro et al, 2002;Wu et al, 2002). Furthermore, transcription of human AMID gene is induced by p53 and expression of AMID is significantly downregulated in some tumors in comparison to their matched normal tissues (Ohiro et al, 2002;Wu et al, 2004).…”