PKR , a p53 target gene, plays a crucial role in the tumor-suppressor function of p53

Abstract

Type I IFN-induced expression of dsRNA-activated protein kinase (PKR) during viral infection is a well-established antiviral mechanism. However, little is known about the expression of PKR in the context of p53 and about PKR involvement in p53-mediated tumor suppression. Here, we report that PKR is a p53 target gene and plays an important role in the tumor-suppressor function of p53. Activation of p53 by genotoxic stress induces a significant level of PKR expression by acting on the newly identified cis-acting element (ISRE), which is separated from the IFN-stimulated responsive element on the PKR promoter, resulting in translational inhibition and cell apoptosis. The genotoxin-mediated inhibition of translation is associated with the p53/PKR/elF2a (eukaryotic initiation factor-2␣) pathway. To some extent, p53 activation induced by DNA damage facilitates cell apoptosis by activating PKR. PKR-knockdown human colon cancer cells grew rapidly in nude mice and proved resistant to anti-cancer drugs. These data indicate that p53-mediated tumor suppression can be attributed at least in part to the biological functions of PKR induced by p53 in genotoxic conditions. p53 tumor suppression ͉ p53RE ͉ translation inhibition and apoptosis

Synthesis of cytochrome c oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death

“…Depletion of SCO2 promotes necrosis formation As our in vitro models might not appropriately reflect the metabolic environment of tumor cells in vivo, we further analyzed the growth of HCT116 p53 , mean±s.d., P40.05) in accordance with previous reports using similar cell numbers (Bhonde et al, 2006;Buzzai et al, 2007;Yoon et al, 2009). Similarly, SCO2-suppressed tumors did not have significant altered doubling times compared with control tumors (6.3 ± 1.52 vs 5.3 ± 0.5 d), but the tumor volumes at the end of the experiment were slightly larger in SCO2-depleted tumors (volumes at day 31 of scrambled sh vs SCO2 sh tumors: 1293 ± 350 vs 1815 ± 641 mm 3 , mean ± s.d., Po0.05; Figure 7b).…”

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

“…Recently, it has been established that PKR is an important downstream effector of p53 in the induction of apoptosis (Yoon et al, 2009). To determine whether this pathway is also able to regulate the expression of TCTP, we made use of a pair of mouse erythroleukaemia cells expressing either a temperature-sensitive mutant form of p53 or a non-activatable mutant p53 (Constantinou and Clemens, 2007).…”

“…PKR has also been implicated in many additional cellular stress responses and corresponding signal transduction pathways, including the nuclear factor-kB and p38-mitogen-activated protein kinase pathways (reviewed by Barber, 2005;Garcia et al, 2006Garcia et al, , 2007. A major role for PKR has recently emerged in the control of apoptosis, following activation of the tumour-suppressor p53 pathway (Yoon et al, 2009). Inhibition of protein synthesis through eIF2a phosphorylation plays a considerable part in PKR activity (Scheuner et al, 2006;Lee et al, 2007), but other pathways are most likely also involved (Garcia et al, 2006).…”

TPT1/ TCTP-regulated pathways in phenotypic reprogramming

“…Although this is an exciting possibility, the physiological significance of these findings remains to be established. Notably, PKR was reported to be a direct transcriptional target of p53 [36], indicating that this tumor suppressor pathway may also be involved indirectly in the control of protein synthesis and of TPT1/TCTP expression via this route ( Figure 2). Thus, it seems reasonable to postulate that the presence of highly structured conformations might be necessary, but not sufficient, to bind/activate PKR.…”

“…PKR phosphorylates eukaryotic initiation factor 2 (eIF2a), thereby stopping the protein translation machinery and inhibiting the translation of TPT1/TCTP. PKR is also directly activated at the transcriptional level by P53 [36]. H5-H6 hairpin of Bax, the H2-H3 hairpin helices of TPT1/ TCTP function as mitochondrial membrane-anchoring motifs to regulate membrane permeability and cytochrome C release during apoptosis.…”