p21WAF1/CIP1 Upregulation through the Stress Granule-Associated Protein CUGBP1 Confers Resistance to Bortezomib-Mediated Apoptosis

Abstract

Backgroundp21WAF1/CIP1 is a well known cyclin-dependent kinase inhibitor induced by various stress stimuli. Depending on the stress applied, p21 upregulation can either promote apoptosis or prevent against apoptotic injury. The stress-mediated induction of p21 involves not only its transcriptional activation but also its posttranscriptional regulation, mainly through stabilization of p21 mRNA levels. We have previously reported that the proteasome inhibitor MG132 induces the stabilization of p21 mRNA, which correlates with the formation of cytoplasmic RNA stress granules. The mechanism underlying p21 mRNA stabilization, however, remains unknown.Methodology/Principal FindingsWe identified the stress granules component CUGBP1 as a factor required for p21 mRNA stabilization following treatment with bortezomib ( = PS-341/Velcade). This peptide boronate inhibitor of the 26S proteasome is very efficient for the treatment of myelomas and other hematological tumors. However, solid tumors are sometimes refractory to bortezomib treatment. We found that depleting CUGBP1 in cancer cells prevents bortezomib-mediated p21 upregulation. FISH experiments combined to mRNA stability assays show that this effect is largely due to a mistargeting of p21 mRNA in stress granules leading to its degradation. Altering the expression of p21 itself, either by depleting CUGBP1 or p21, promotes bortezomib-mediated apoptosis.Conclusions/SignificanceWe propose that one key mechanism by which apoptosis is inhibited upon treatment with chemotherapeutic drugs might involve upregulation of the p21 protein through CUGBP1.

Arginylated Calreticulin at Plasma Membrane Increases Susceptibility of Cells to Apoptosis

“…The choice between these two responses is dictated by the intensity of stress, as well as cellintrinsic parameters, for instance those that set the apoptotic threshold. It is of interest to mention that the formation of SGs upon exposure to hypoxia (47) or oxidative stress (48) leads to tumor cell resistance to apoptosis, by a mechanism that involves the sequestration and inactivation of proapoptotic proteins in SGs (49). It is an intriguing possibility that arginylation may participate in this cancer process.…”

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

“…Les globines en excès ont tendance à précipi-ter et à former des inclusions toxiques [20,23], provoquant la lyse des globules rouges et donc une anémie [22]. peuvent aussi interférer avec l'apoptose via la stabilisation d'ARNm codant pour des protéines intervenant dans la survie cellulaire, telles que les cytokines ou p21 [4,8]. De plus, en séquestrant les facteurs d'initiation de la traduction, les granules de stress contribuent à la répression de cette dernière.…”

“…Plusieurs études ont aussi démontré l'intervention, dans la diminution de la sensibilité cellulaire à certaines drogues ou l'échappement des cellules aux contrôles du cycle cellulaire, d'une reprogrammation de certaines voies de signalisation ciblées par ces drogues, même si ces dernières induisaient des dommages à l'ADN [1][2][3]. Plus récemment, un mécanisme de résistance à l'apoptose induite par les radiations [4] et par les drogues chimiothé-rapeutiques a été mis en évidence [5][6][7][8] ; il implique la formation de granules de stress anti-apoptotiques. Les granules de stress sont des corps cytoplasmiques non membranaires et dynamiques constitués, entre autres, d'ARNm, de protéines de liaison à l'ARN, et de molécules de signalisation intervenant dans la mort cellulaire.…”

The role of the 3' untranslated region in post-transcriptional regulation of protein expression in mammalian cells.

“…95 Moreover, CUGBP1 has been identified as a new TTR-RBP member due to its auto-regulatory capacity and association with other RNA-binding proteins such as the splicing factors, PABPN1, PABPC4, HuR or Pum1.…”