title: p21(WAF1/CIP1) upregulation through the stress granule-associated protein CUGBP1 confers resistance to bortezomib-mediated apoptosis.
abstract: BACKGROUND
  p21(WAF1/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.
  
  
  RESULTS
  We 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
  We propose that one key mechanism by which apoptosis is inhibited upon treatment with chemotherapeutic drugs might involve upregulation of the p21 protein through CUGBP1.
authors.affiliation: Department of Molecular Biology, Medical Biochemistry, and Pathology, Faculty of Medicine, Laval University, CHUQ Research Centre/St-François d'Assise Research Centre (CRCHUQ/CRSFA), Quebec, Canada.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gareau
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Fournier
authors.forename: Christine
authors.initials: C
authors.lastname: Filion
authors.forename: Laetitia
authors.initials: L
authors.lastname: Coudert
authors.forename: David
authors.initials: D
authors.lastname: Martel
authors.forename: Yves
authors.initials: Y
authors.lastname: Labelle
authors.forename: Rachid
authors.initials: R
authors.lastname: Mazroui
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D000067879:CELF1 Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D001897:Boronic Acids; D000067879:CELF1 Protein; C102843:CELF1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011719:Pyrazines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000069286:Bortezomib