title: A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase.
abstract: Dysregulated Raf/MEK/extracellular signal-regulated kinase (ERK) signaling, a common hallmark of tumorigenesis, can trigger innate tumor-suppressive mechanisms, which must be inactivated for carcinogenesis to occur. This innate tumor-suppressive signaling may provide a potential therapeutic target. Here we report that mortalin (HSPA9/GRP75/PBP74) is a novel negative regulator of Raf/MEK/ERK and may provide a target for the reactivation of tumor-suppressive signaling of the pathway in cancer. We found that mortalin is present in the MEK1/MEK2 proteome and is upregulated in human melanoma biopsy specimens. In different MEK/ERK-activated cancer cell lines, mortalin depletion induced cell death and growth arrest, which was accompanied by increased p21(CIP1) transcription and MEK/ERK activity. Remarkably, MEK/ERK activity was necessary for mortalin depletion to induce p21(CIP1) expression in B-Raf(V600E)-transformed cancer cells regardless of their p53 status. In contrast, in cell types exhibiting normal MEK/ERK status, mortalin overexpression suppressed B-Raf(V600E)- or ΔRaf-1:ER-induced MEK/ERK activation, p21(CIP1) expression, and cell cycle arrest. Other HSP70 family chaperones could not effectively replace mortalin for p21(CIP1) regulation, suggesting a unique role for mortalin. These findings reveal a novel mechanism underlying p21(CIP1) regulation in MEK/ERK-activated cancer and identify mortalin as a molecular switch that mediates the tumor-suppressive versus oncogenic result of dysregulated Raf/MEK/ERK signaling. Our study also demonstrates that p21(CIP1) has dual effects under mortalin-depleted conditions, i.e., mediating cell cycle arrest while limiting cell death.
authors: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Pui-Kei
authors: PK
authors: Wu
authors: Seung-Keun
authors: SK
authors: Hong
authors: Sudhakar
authors: S
authors: Veeranki
authors: Mansi
authors: M
authors: Karkhanis
authors: Dmytro
authors: D
authors: Starenki
authors: Jose A
authors: JA
authors: Plaza
authors: Jong-In
authors: JI
authors: Park
mesh_terms: D059447:Cell Cycle Checkpoints; D016923:Cell Death; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008156:Luciferases; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018840:HSP70 Heat-Shock Proteins; D016159:Tumor Suppressor Protein p53; C080352:mortalin; D008156:Luciferases; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
references: J Biol Chem. 2011 Jul 29;286(30):26860-72
references: 21642427
references: Nature. 2007 Feb 8;445(7128):661-5
references: 17251932
references: Cell. 1997 Mar 7;88(5):593-602
references: 9054499
references: J Biol Chem. 1999 Oct 15;274(42):30273-9
references: 10514521
references: Cancer Cell. 2012 Mar 20;21(3):297-308
references: 22439925
references: Mol Cell Biol. 1993 Oct;13(10):6241-52
references: 8413224
references: N Engl J Med. 2006 Sep 7;355(10):1037-46
references: 16957149
references: Science. 1998 Nov 20;282(5393):1497-501
references: 9822382
references: J Invest Dermatol. 2012 Feb;132(2):356-64
references: 21993556
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Cytometry. 1983 Mar;3(5):323-7
references: 6188586
references: Biochim Biophys Acta. 2007 Aug;1773(8):1213-26
references: 17112607
references: Oncogene. 2009 Dec 3;28(48):4284-94
references: 19749793
references: Cell. 1998 Feb 6;92(3):351-66
references: 9476895
references: Exp Cell Res. 2011 Nov 1;317(18):2671-82
references: 21871886
references: Cell Cycle. 2010 May 15;9(10):1972-80
references: 20495378
references: Am J Pathol. 2006 Jun;168(6):1838-47
references: 16723699
references: N Engl J Med. 2011 Feb 24;364(8):772-4
references: 21345109
references: Cell. 1992 Nov 27;71(5):875-86
references: 1423635
references: Nature. 2005 Aug 4;436(7051):720-4
references: 16079850
references: Nat Rev Mol Cell Biol. 2010 Aug;11(8):579-92
references: 20651708
references: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references: 17126425
references: J Gene Med. 2004 Apr;6(4):439-44
references: 15079818
references: Biochem J. 2005 Oct 15;391(Pt 2):185-90
references: 15957980
references: Oncogene. 2007 May 14;26(22):3291-310
references: 17496923
references: J Biol Chem. 1995 Sep 1;270(35):20801-7
references: 7657664
references: Nat Genet. 2003 Mar;33(3):401-6
references: 12590264
references: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16406-11
references: 17062750
references: J Biol Chem. 2004 Nov 19;279(47):48836-45
references: 15358769
references: Ann N Y Acad Sci. 2007 Nov;1119:165-75
references: 18056964
references: Cancer Lett. 1997 Nov 11;119(2):185-90
references: 9570370
references: Cell. 2007 Jan 26;128(2):295-308
references: 17254968
references: J Biol Chem. 1998 Nov 6;273(45):29586-91
references: 9792667
references: FEBS Lett. 2007 Jul 31;581(19):3702-10
references: 17544402
references: Cell. 2011 Jan 7;144(1):119-31
references: 21215374
references: Biochim Biophys Acta. 2011 Dec;1816(2):89-104
references: 21605630
references: Free Radic Biol Med. 2006 Aug 15;41(4):601-9
references: 16863993
references: J Biol Chem. 2009 Nov 27;284(48):33006-18
references: 19805545
references: J Biol Chem. 2012 May 11;287(20):16168-78
references: 22427654
references: Cell Death Differ. 2011 Jun;18(6):1046-56
references: 21233847
references: Int J Cancer. 2006 Jun 15;118(12):2973-80
references: 16425258
references: Biochim Biophys Acta. 2013 Jul;1833(7):1755-65
references: 23360981
references: J Biol Chem. 2002 Oct 4;277(40):37949-54
references: 12151395
references: Nature. 2005 Aug 4;436(7051):660-5
references: 16079837
references: Nature. 2005 Aug 4;436(7051):642
references: 16079833
references: Biochem Biophys Res Commun. 2003 Mar 21;302(4):735-42
references: 12646231
references: Exp Gerontol. 2007 Apr;42(4):263-74
references: 17188442
references: Cell Signal. 2011 Jan;23(1):6-13
references: 20633638
references: Biochim Biophys Acta. 2012 Apr;1825(2):229-44
references: 22333261
references: Oncogene. 2008 May 1;27(20):2801-9
references: 18193093
references: Nat Genet. 1994 Sep;8(1):15-21
references: 7987387
references: Genes Dev. 1998 Oct 1;12(19):2997-3007
references: 9765202
references: Nature. 2007 Feb 8;445(7128):656-60
references: 17251933
references: Cancer Res. 2008 May 1;68(9):3429-39
references: 18451171
references: Cancer Res. 2007 Dec 15;67(24):11779-88
references: 18089808
references: Genes Dev. 1998 Oct 1;12(19):3008-19
references: 9765203
references: Oncogene. 2010 Apr 1;29(13):1952-62
references: 20062073
references: Nat Rev Cancer. 2009 Jun;9(6):400-14
references: 19440234