SKP2 oncogene is a direct MYC target gene and MYC down-regulates p27(KIP1) through SKP2 in human leukemia cells.
SKP2 is the ubiquitin ligase subunit that targets p27(KIP1) (p27) for degradation. SKP2 is induced in the G(1)-S transit of the cell cycle, is frequently overexpressed in human cancer, and displays transformation activity in experimental models. Here we show that MYC induces SKP2 expression at the mRNA and protein levels in human myeloid leukemia K562 cells with conditional MYC expression. Importantly, in these systems, induction of MYC did not activate cell proliferation, ruling out SKP2 up-regulation as a consequence of cell cycle entry. MYC-dependent SKP2 expression was also detected in other cell types such as lymphoid, fibroblastic, and epithelial cell lines. MYC induced SKP2 mRNA expression in the absence of protein synthesis and activated the SKP2 promoter in luciferase reporter assays. With chromatin immunoprecipitation assays, MYC was detected bound to a region of human SKP2 gene promoter that includes E-boxes. The K562 cell line derives from human chronic myeloid leukemia. In a cohort of chronic myeloid leukemia bone marrow samples, we found a correlation between MYC and SKP2 mRNA levels. Analysis of cancer expression databases also indicated a correlation between MYC and SKP2 expression in lymphoma. Finally, MYC-induced SKP2 expression resulted in a decrease in p27 protein in K562 cells. Moreover, silencing of SKP2 abrogated the MYC-mediated down-regulation of p27. Our data show that SKP2 is a direct MYC target gene and that MYC-mediated SKP2 induction leads to reduced p27 levels. The results suggest the induction of SKP2 oncogene as a new mechanism for MYC-dependent transformation.
Departamento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria, Consejo Superior de Investigaciones Científicas, SODERCAN (Sociedad para el Desarrollo de Cantabria), 39011 Santander, Spain.
Gabriel
G
Bretones
Juan C
JC
Acosta
Juan M
JM
Caraballo
Nuria
N
Ferrándiz
M Teresa
MT
Gómez-Casares
Marta
M
Albajar
Rosa
R
Blanco
Paula
P
Ruiz
Wen-Chun
WC
Hung
M Pilar
MP
Albero
Ignacio
I
Perez-Roger
Javier
J
León
D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D005260:Female; D016193:G1 Phase / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D016196:S Phase / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases
Cell Cycle. 2009 Apr 15;8(8):1148-57
19282668
Chem Biol. 2006 Jul;13(7):745-51
16873022
J Clin Oncol. 2009 Dec 10;27(35):6041-51
19884523
J Biol Chem. 2005 May 6;280(18):18120-9
15746092
Nat Immunol. 2010 Mar;11(3):207-15
20081848
EMBO J. 1990 Apr;9(4):1113-21
2182320
Genes Dev. 2000 Sep 1;14(17):2185-91
10970882
J Clin Invest. 2003 Dec;112(11):1724-31
14660748
EMBO J. 1999 Oct 1;18(19):5321-33
10508165
Oncogene. 1999 May 13;18(19):3004-16
10378696
Biochim Biophys Acta. 2002 Mar 14;1602(1):61-71
11960695
EMBO Rep. 2007 Jan;8(1):70-6
17159920
Nat Rev Cancer. 2008 Dec;8(12):976-90
19029958
Nat Rev Cancer. 2007 Jun;7(6):441-53
17522713
Nat Rev Cancer. 2006 May;6(5):369-81
16633365
Cell Growth Differ. 1999 Sep;10(9):639-54
10511314
Nat Cell Biol. 2004 Dec;6(12):1229-35
15531880
Science. 1995 Aug 4;269(5224):682-5
7624798
Int J Cancer. 2000 Sep 15;87(6):787-93
10956386
J Immunol. 2004 May 1;172(9):5522-7
15100294
J Biol Chem. 2001 Dec 28;276(52):48937-43
11682478
Genes Dev. 2008 Oct 15;22(20):2755-66
18923074
J Cell Physiol. 2000 Apr;183(1):10-7
10699961
Mol Cell Biol. 2008 Dec;28(24):7286-95
18838534
J Cell Physiol. 2006 Nov;209(2):363-9
16883603
Leuk Res. 2009 Nov;33(11):1520-4
19329185
Blood. 2008 Sep 1;112(5):1960-70
18559973
Mol Cell Biol. 2004 Jul;24(13):5923-36
15199147
EMBO J. 2007 May 16;26(10):2562-74
17464290
Nat Cell Biol. 1999 Aug;1(4):207-14
10559918
Cell. 1994 Jul 15;78(1):59-66
8033212
Mol Cell Biol. 1999 Sep;19(9):5913-22
10454538
Cancer. 2008 Apr 1;112(7):1415-24
18260093
Science. 1996 May 10;272(5263):877-80
8629023
Genes Cancer. 2010 Jun;1(6):605-16
21779460
Cell Growth Differ. 1997 Oct;8(10):1039-48
9342182
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8164-9
12808131
EMBO J. 1999 Oct 1;18(19):5310-20
10508164
Biochemistry. 2008 Jul 22;47(29):7598-609
18627125
Cancer Res. 2005 Apr 15;65(8):3264-72
15833859
Nat Cell Biol. 1999 Aug;1(4):193-9
10559916
Oncogene. 2000 Apr 27;19(18):2194-204
10822369
EMBO J. 1990 Dec;9(12):3913-22
2249657
Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17834-9
17093053
Nucleic Acids Res. 1995 May 25;23(10):1686-90
7784172
Mol Cell. 2003 May;11(5):1177-88
12769843
Genes Dev. 2004 Nov 1;18(21):2602-7
15520280
Semin Cancer Biol. 2006 Aug;16(4):253-64
16904903
Mol Cancer Res. 2010 Mar;8(3):353-62
20197382
EMBO J. 2002 Jul 15;21(14):3739-48
12110586
Dev Cell. 2004 May;6(5):661-72
15130491
Oncogene. 2002 Oct 17;21(47):7137-46
12370803
Nat Rev Cancer. 2004 Jul;4(7):562-8
15229481
Oncogene. 2001 Mar 29;20(14):1688-702
11313917
Curr Biol. 1999 Nov 4;9(21):1255-8
10556095
Cell. 2010 Oct 15;143(2):313-24
20946988
Genome Biol. 2008;9(9):R139
18803840
Oncogene. 1995 Apr 20;10(8):1659-65
7731722
PLoS One. 2008 Mar 12;3(3):e1798
18335064
Haematologica. 2004 Feb;89(2):241-3
15003904
Cancer Sci. 2009 Aug;100(8):1374-81
19459846
EMBO J. 1996 Aug 15;15(16):4344-57
8861962
Nat Rev Cancer. 2008 Jun;8(6):438-49
18500245
Mol Cell. 2003 May;11(5):1189-200
12769844
Genes Dev. 2003 May 1;17(9):1101-14
12695332
Cell. 2000 Dec 8;103(6):843-52
11136970
Curr Biol. 1999 Jun 17;9(12):661-4
10375532
Genes Dev. 2003 May 1;17(9):1115-29
12695333
Genes Dev. 2008 Nov 15;22(22):3121-34
19056892
Cell Cycle. 2010 Jun 15;9(12):2342-52
20519948
FEBS Lett. 1999 Feb 5;444(1):5-10
10037138
Nat Rev Cancer. 2008 Apr;8(4):253-67
18354415