title: Stabilization of p21 by mTORC1/4E-BP1 predicts clinical outcome of head and neck cancers.
abstract: The levels, regulation and prognostic value of p21 in head and neck squamous cell carcinomas (HNSCC) has been puzzling for years. Here, we report a new mechanism of regulation of p21 by the mTORC1/4E-BP1 pathway. We find that non-phosphorylated 4E-BP1 interacts with p21 and induces its degradation. Accordingly, hyper-activation of mTORC1 results in phosphorylation of 4E-BP1 and stabilization of p21. In HNSCC, p21 levels strongly correlate with mTORC1 activity but not with p53 status. Finally, clinical data indicate that HNSCC patients with p21 and phospho-S6-double-positive tumours present a better disease-specific survival. We conclude that over-activation of the mTORC1/4E-BP1/p21 pathway is a frequent and clinically relevant alteration in HNSCC.
authors.affiliation: Tumor Suppression Group, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernandez Almagro Street, Madrid 28029, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Llanos
authors.affiliation: Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo 33006, Spain.
authors.forename: Juana M
authors.initials: JM
authors.lastname: García-Pedrero
authors.affiliation: Tumor Suppression Group, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernandez Almagro Street, Madrid 28029, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morgado-Palacin
authors.affiliation: Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo 33006, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Rodrigo
authors.affiliation: Tumor Suppression Group, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernandez Almagro Street, Madrid 28029, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C087000:EIF4EBP1 protein, human; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
references.citation: Arch Otolaryngol Head Neck Surg. 1994 Jul;120(7):750-4
references.pmid: 8018328
references.citation: PLoS One. 2014;9(8):e106098
references.pmid: 25165983
references.citation: Cell. 1997 Mar 7;88(5):593-602
references.pmid: 9054499
references.citation: J Biol Chem. 2009 Mar 20;284(12):8023-32
references.pmid: 19150980
references.citation: Int J Cancer. 1997 Aug 22;74(4):383-9
references.pmid: 9291426
references.citation: Mod Pathol. 2013 Mar;26(3):327-35
references.pmid: 22996377
references.citation: Int J Mol Sci. 2014;15(11):20753-69
references.pmid: 25402640
references.citation: Cell Prolif. 1996 May;29(5):219-30
references.pmid: 8782485
references.citation: Cell. 2005 Mar 25;120(6):747-59
references.pmid: 15797377
references.citation: Cancer Discov. 2013 Jul;3(7):761-9
references.pmid: 23619167
references.citation: Nature. 2012 May 3;485(7396):109-13
references.pmid: 22552098
references.citation: J Oral Pathol Med. 1998 Sep;27(8):367-75
references.pmid: 9736425
references.citation: In Vivo. 2004 Nov-Dec;18(6):719-24
references.pmid: 15646812
references.citation: J Clin Invest. 2010 Mar;120(3):681-93
references.pmid: 20197621
references.citation: Science. 2013 Jul 26;341(6144):1236566
references.pmid: 23888043
references.citation: Med Oral Patol Oral Cir Bucal. 2013 Mar;18(2):e219-25
references.pmid: 23385498
references.citation: Nat Rev Cancer. 2011 Jan;11(1):9-22
references.pmid: 21160525
references.citation: Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
references.pmid: 19339977
references.citation: Int J Cancer. 2005 Mar 20;114(2):242-8
references.pmid: 15543611
references.citation: Mod Pathol. 2012 Aug;25(8):1069-78
references.pmid: 22460808
references.citation: J Pathol. 1997 Oct;183(2):156-63
references.pmid: 9390027
references.citation: Cancer Discov. 2013 Jul;3(7):770-81
references.pmid: 23619168
references.citation: Cell Signal. 2010 Jul;22(7):1003-12
references.pmid: 20100570
references.citation: Sci Signal. 2009;2(89):ra57
references.pmid: 19797274
references.citation: Nature. 1998 Sep 10;395(6698):125-6
references.pmid: 9744268
references.citation: Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35
references.pmid: 21157483
references.citation: Mol Cell. 2012 Jun 29;46(6):847-58
references.pmid: 22578813
references.citation: Oral Dis. 2015 Oct;21(7):815-25
references.pmid: 24219320
references.citation: Curr Opin Cell Biol. 2010 Dec;22(6):816-27
references.pmid: 20807678
references.citation: Oral Oncol. 1998 May;34(3):198-203
references.pmid: 9692054
references.citation: EMBO J. 2010 Sep 1;29(17):2994-3006
references.pmid: 20657550
references.citation: J Clin Pathol. 2014 Nov;67(11):961-7
references.pmid: 25053543
references.citation: J Clin Invest. 2003 Oct;112(8):1223-33
references.pmid: 14561707
references.citation: J Cell Sci. 2013 Apr 15;126(Pt 8):1713-9
references.pmid: 23641065
references.citation: Curr Opin Oncol. 2013 Jan;25(1):52-8
references.pmid: 23159848
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: Int J Cancer. 2014 Jan 15;134(2):487-92
references.pmid: 23824638
references.citation: Head Neck. 1992 May-Jun;14(3):196-9
references.pmid: 1587736
references.citation: Nat Cell Biol. 2013 Jun;15(6):555-64
references.pmid: 23728461
references.citation: Oncogene. 2012 Apr 12;31(15):1949-62
references.pmid: 21909130
references.citation: Cell Stem Cell. 2014 May 1;14(5):606-16
references.pmid: 24630793
references.citation: Clin Cancer Res. 2014 Apr 1;20(7):1946-54
references.pmid: 24366692
references.citation: Cancer. 1991 Jun 1;67(11):2741-7
references.pmid: 2025837
references.citation: J Cancer Res Clin Oncol. 1995;121(8):452-6
references.pmid: 7642686
references.citation: Nat Rev Cancer. 2009 Jun;9(6):400-14
references.pmid: 19440234
references.citation: J Carcinog Mutagen. 2013 Aug 2;Suppl 5:null
references.pmid: 25126449
references.citation: Virchows Arch. 2012 Jun;460(6):601-9
references.pmid: 22562131
references.citation: Cancer Epidemiol. 2015 Feb;39(1):37-41
references.pmid: 25468644
references.citation: Science. 2011 Aug 26;333(6046):1157-60
references.pmid: 21798893