title: p53 and translation attenuation regulate distinct cell cycle checkpoints during endoplasmic reticulum (ER) stress.
abstract: Cell cycle checkpoints ensure that proliferation occurs only under permissive conditions, but their role in linking nutrient availability to cell division is incompletely understood. Protein folding within the endoplasmic reticulum (ER) is exquisitely sensitive to energy supply and amino acid sources because deficiencies impair luminal protein folding and consequently trigger ER stress signaling. Following ER stress, many cell types arrest within the G(1) phase, although recent studies have identified a novel ER stress G(2) checkpoint. Here, we report that ER stress affects cell cycle progression via two classes of signal: an early inhibition of protein synthesis leading to G(2) delay involving CHK1 and a later induction of G(1) arrest associated both with the induction of p53 target genes and loss of cyclin D(1). We show that substitution of p53/47 for p53 impairs the ER stress G(1) checkpoint, attenuates the recovery of protein translation, and impairs induction of NOXA, a mediator of cell death. We propose that cell cycle regulation in response to ER stress comprises redundant pathways invoked sequentially first to impair G(2) progression prior to ultimate G(1) arrest.
authors: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors: Sally E
authors: SE
authors: Thomas
authors: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom; Department of Genetics, University of Cambridge, Downing Site, Cambridge CB2 3EH, United Kingdom.
authors: Elke
authors: E
authors: Malzer
authors: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors: Adriana
authors: A
authors: Ordóñez
authors: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors: Lucy E
authors: LE
authors: Dalton
authors: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors: Emily F A
authors: EFA
authors: van T Wout
authors: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors: Elizabeth
authors: E
authors: Liniker
authors: Department of Genetics, University of Cambridge, Downing Site, Cambridge CB2 3EH, United Kingdom.
authors: Damian C
authors: DC
authors: Crowther
authors: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors: David A
authors: DA
authors: Lomas
authors: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom. Electronic address: sjm20@cam.ac.uk.
authors: Stefan J
authors: SJ
authors: Marciniak
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D004331:Drosophila melanogaster; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D016158:Genes, p53; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000378:metabolism; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1