Cdk2: a key regulator of the senescence control function of Myc.
Proto-oncogenes such as MYC and RAS promote normal cell growth but fuel tumor development when deregulated. However, over-activated Myc and Ras also trigger intrinsic tumor suppressor mechanisms leading to apoptosis and senescence, respectively. When expressed together MYC and RAS are sufficient for oncogenic transformation of primary rodent cells, but the basis for their cooperativity has remained unresolved. While Ras is known to suppress Myc-induced apoptosis, we recently discovered that Myc is able to repress Ras-induced senescence. Myc and Ras thereby together enable evasion of two main barriers of tumorigenesis. The ability of Myc to suppress senescence was dependent on phosphorylation of Myc at Ser 62 by cyclin-dependent kinase 2 (Cdk2), uncovering a new non-redundant role of this kinase. Further, utilizing Cdk2 as a cofactor, Myc directly controlled key genes involved in senescence. We speculate that this new role of Myc/Cdk2 in senescence has relevance for other Myc functions, such as regulation of stemness, self-renewal, immortalization and differentiation, which may have an impact on tissue regeneration. Importantly, selective pharmacological inhibition of Cdk2 forced Myc/Ras expressing cells into cellular senescence, highlighting this kinase as a potential therapeutic target for treatment of tumors driven by Myc or Ras.
Hydbring
Per
P
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
Larsson
Lars-Gunnar
LG
D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2 / Q000502:physiology*; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology
D016271:Proto-Oncogene Proteins c-myc; D051357:Cyclin-Dependent Kinase 2; D018631:ras Proteins
Nature. 2006 Nov 30;444(7119):638-42
17136094
Oncogene. 2008 Nov 6;27(52):6623-34
18679422
Nature. 2005 Aug 4;436(7051):660-5
16079837
Nature. 2006 Sep 28;443(7110):453-7
16957737
Nature. 2006 Nov 30;444(7119):633-7
17136093
Genes Dev. 2004 Nov 15;18(22):2699-711
15545627
Nature. 2007 Jul 26;448(7152):445-51
17597761
Nature. 2007 Jul 19;448(7151):375-9
17637672
Genes Dev. 1998 Aug 1;12(15):2424-33
9694806
Annu Rev Cell Dev Biol. 2000;16:653-99
11031250
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3645-50
16537449
Cell. 1997 Mar 7;88(5):593-602
9054499
Nature. 2004 Nov 18;432(7015):307-15
15549092
Nature. 2005 Aug 4;436(7051):720-4
16079850
Nat Rev Mol Cell Biol. 2007 Apr;8(4):275-83
17380161
Exp Cell Res. 2010 May 1;316(8):1429-37
20382143
Aging Cell. 2006 Oct;5(5):379-89
16911562
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13028-33
17664422
Cancer Res. 2006 Aug 15;66(16):8219-26
16912201
Nat Genet. 2003 Sep;35(1):25-31
12923533
Genes Dev. 2002 Oct 15;16(20):2699-712
12381668
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3826-31
11274400
Nat Rev Mol Cell Biol. 2008 Jul;9(7):517-31
18568040
Cell Cycle. 2007 Dec 1;6(23):2902-5
17993782
Genes Dev. 2004 Feb 1;18(3):306-19
14871929
Cancer Res. 2006 Jul 1;66(13):6598-605
16818632
Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40
17667954
Cell. 2008 Nov 14;135(4):609-22
19013273
Mol Cell. 2002 May;9(5):1031-44
12049739
J Biol Chem. 2006 Nov 17;281(46):34725-9
16987807
Nature. 1997 Feb 6;385(6616):544-8
9020362
Nat Cell Biol. 2010 Jan;12(1):54-9; sup pp 1-14
20010815
Nature. 2006 Sep 28;443(7110):421-6
16957735
Nat Rev Cancer. 2010 Jan;10(1):51-7
20029423
Nat Med. 2007 Jul;13(7):820-7
17589519
Cell. 2007 Jul 27;130(2):223-33
17662938
Nature. 2002 Oct 17;419(6908):729-34
12384701
Nature. 2005 Aug 4;436(7051):642
16079833
Nature. 2005 Aug 11;436(7052):807-11
16094360
Mol Cell. 2006 Feb 17;21(4):509-19
16483932
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):58-63
19966300
Mol Cell. 2002 Sep;10(3):509-21
12408820
Nature. 2002 Jan 3;415(6867):45-53
11780111
Nat Rev Cancer. 2009 Jul;9(7):501-7
19550425
Cancer Cell. 2007 May;11(5):461-9
17433785
Oncogene. 2003 Jan 23;22(3):351-60
12545156
Cell Stem Cell. 2008 Dec 4;3(6):611-24
19041778
Development. 2005 Mar;132(5):885-96
15673569
Cell. 2002 May 3;109(3):335-46
12015983
Genes Dev. 2003 Jul 1;17(13):1569-74
12842909
Nature. 2006 Sep 28;443(7110):448-52
16957738
Science. 2000 Mar 10;287(5459):1804-8
10710306