title: Regulation of vascular smooth muscle proliferation by heparin: inhibition of cyclin-dependent kinase 2 activity by p27(kip1).
abstract: Uncontrolled proliferation of vascular smooth muscle cells (VSMCs) contribute to intimal hyperplasia during atherosclerosis and restenosis. Heparin is an antiproliferative agent for VSMCs and has been shown to block VSMC proliferation both in tissue culture systems and in animals. Despite the well documented antiproliferative actions of heparin, its cellular targets largely remain unknown. In an effort to characterize the mechanism of the antiproliferative property of heparin, we have analyzed the effect of heparin on cell cycle in VSMC. Our results indicate that the heparin-induced block in G(1) to S phase transition is imposed by p27(kip1)-mediated inhibition of cyclin-dependent kinase 2 activity. Further analysis of p27(kip1) mRNA levels showed that the increase in p27(kip1) protein levels in heparin-treated VSMC occurs at posttranscriptional levels. We present evidence that heparin causes stabilization of p27(kip1) protein during G(1) phase and thereby prevents activation of cyclin-dependent kinase 2.
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fasciano
authors.forename: Rekha C
authors.initials: RC
authors.lastname: Patel
authors.forename: Indhira
authors.initials: I
authors.lastname: Handy
authors.forename: Chandrashekhar V
authors.initials: CV
authors.lastname: Patel
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D019925:Cyclin A / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006493:Heparin / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006493:Heparin
references.citation: J Biol Chem. 2001 Dec 28;276(52):48937-43
references.pmid: 11682478
references.citation: Dev Biol. 2002 May 1;245(1):224-34
references.pmid: 11969268
references.citation: Lab Invest. 2001 Jun;81(6):895-903
references.pmid: 11406650
references.citation: Atherosclerosis. 2004 Jan;172(1):31-8
references.pmid: 14709354
references.citation: J Cell Biol. 1981 Aug;90(2):372-9
references.pmid: 7287812
references.citation: Am J Pathol. 1990 Aug;137(2):313-30
references.pmid: 2386199
references.citation: Prog Cell Cycle Res. 1995;1:115-23
references.pmid: 9552357
references.citation: J Cell Biol. 1989 Dec;109(6 Pt 1):3147-55
references.pmid: 2592420
references.citation: Mol Cell Biol. 1988 Oct;8(10):4289-94
references.pmid: 2460741
references.citation: Eur J Biochem. 2002 Jun;269(11):2810-9
references.pmid: 12047392
references.citation: J Clin Invest. 1997 May 15;99(10):2334-41
references.pmid: 9153274
references.citation: Biochim Biophys Acta. 2002 Mar 14;1602(1):73-87
references.pmid: 11960696
references.citation: EMBO J. 2001 Dec 3;20(23):6672-82
references.pmid: 11726503
references.citation: J Invasive Cardiol. 2000 Dec;12 Suppl F:20F-6
references.pmid: 11156730
references.citation: Cancer Cell. 2003 Feb;3(2):111-5
references.pmid: 12620406
references.citation: J Biol Chem. 2004 Sep 3;279(36):37670-6
references.pmid: 15229216
references.citation: Cell. 1996 May 31;85(5):707-20
references.pmid: 8646779
references.citation: Nat Rev Cancer. 2003 Feb;3(2):130-8
references.pmid: 12563312
references.citation: Am J Pathol. 1994 Jun;144(6):1348-56
references.pmid: 8203472
references.citation: FASEB J. 2001 Sep;15(11):1989-95
references.pmid: 11532979
references.citation: J Invasive Cardiol. 2000 Dec;12 Suppl E:E14-8;discussion E25-8
references.pmid: 11156724
references.citation: Nature. 2001 Sep 20;413(6853):323-7
references.pmid: 11565035
references.citation: Science. 1995 Aug 4;269(5224):682-5
references.pmid: 7624798
references.citation: J Biol Chem. 1996 Aug 2;271(31):18337-41
references.pmid: 8702474
references.citation: J Clin Invest. 1995 Nov;96(5):2260-8
references.pmid: 7593612
references.citation: Genes Dev. 1995 May 15;9(10):1149-63
references.pmid: 7758941
references.citation: Circ Res. 1992 May;70(5):1062-9
references.pmid: 1314715
references.citation: J Biol Chem. 1992 Feb 25;267(6):3707-11
references.pmid: 1371276
references.citation: Cell. 2004 Jan 23;116(2):221-34
references.pmid: 14744433
references.citation: J Biol Chem. 2003 Feb 14;278(7):4482-90
references.pmid: 12477734
references.citation: Transplant Proc. 2003 May;35(3 Suppl):231S-233S
references.pmid: 12742501
references.citation: Exp Cell Res. 1998 May 1;240(2):218-27
references.pmid: 9596994
references.citation: J Biol Chem. 2002 Jan 18;277(3):1924-7
references.pmid: 11706028
references.citation: J Vasc Surg. 1998 Mar;27(3):512-20
references.pmid: 9546238
references.citation: Circulation. 1999 Apr 27;99(16):2164-70
references.pmid: 10217658
references.citation: Genes Dev. 2002 Dec 1;16(23):3087-99
references.pmid: 12464637
references.citation: J Biol Chem. 2004 May 21;279(21):22498-504
references.pmid: 15010468
references.citation: Am J Pathol. 2002 Nov;161(5):1893-901
references.pmid: 12414535
references.citation: Mol Cell Biol. 1999 Feb;19(2):1190-201
references.pmid: 9891053
references.citation: Mol Hum Reprod. 1999 Feb;5(2):139-45
references.pmid: 10065869
references.citation: Circulation. 2001 Jun 19;103(24):2967-72
references.pmid: 11413088
references.citation: Nature. 1998 Nov 12;396(6707):177-80
references.pmid: 9823898
references.citation: Nat Cell Biol. 1999 Aug;1(4):207-14
references.pmid: 10559918
references.citation: Science. 1996 Mar 29;271(5257):1861-4
references.pmid: 8596954
references.citation: Nature. 1995 Mar 9;374(6518):131-4
references.pmid: 7877684
references.citation: Genes Dev. 1999 May 1;13(9):1181-9
references.pmid: 10323868
references.citation: J Cell Biol. 2000 Feb 7;148(3):543-56
references.pmid: 10662779
references.citation: EMBO J. 2002 Jul 1;21(13):3390-401
references.pmid: 12093740
references.citation: Sci STKE. 2002 May 28;2002(134):re7
references.pmid: 12034920
references.citation: Am J Physiol. 1999 Oct;277(4):C652-64
references.pmid: 10516095
references.citation: Circ Res. 2000 Jul 21;87(2):92-8
references.pmid: 10903991
references.citation: J Clin Invest. 1999 Sep;104(6):815-23
references.pmid: 10491417
references.citation: Proc Natl Acad Sci U S A. 1989 May;86(9):3199-203
references.pmid: 2541434
references.citation: Circ Res. 1997 Jul;81(1):17-23
references.pmid: 9201023
references.citation: Blood. 2004 Jan 1;103(1):158-61
references.pmid: 14504088
references.citation: J Biol Chem. 2000 Aug 18;275(33):25146-54
references.pmid: 10831586
references.citation: Nat Cell Biol. 1999 Aug;1(4):193-9
references.pmid: 10559916
references.citation: Eur J Biochem. 1997 Aug 15;248(1):1-9
references.pmid: 9310352
references.citation: FASEB J. 2001 Sep;15(11):1877-85
references.pmid: 11532967
references.citation: Int Angiol. 1987 Jan-Mar;6(1):45-51
references.pmid: 3624946
references.citation: Mol Cell Biol. 2000 Aug;20(16):5947-59
references.pmid: 10913178
references.citation: Circ Res. 1998 Feb 23;82(3):396-403
references.pmid: 9486668
references.citation: J Clin Invest. 1994 May;93(5):1987-93
references.pmid: 8182130
references.citation: Nature. 2002 Dec 19-26;420(6917):868-74
references.pmid: 12490960
references.citation: J Biol Chem. 1996 Jul 19;271(29):17100-6
references.pmid: 8663360
references.citation: J Biol Chem. 2002 Apr 26;277(17):14355-8
references.pmid: 11889117
references.citation: Transplant Proc. 1989 Aug;21(4):3700-1
references.pmid: 2763338
references.citation: J Biol Chem. 2002 Sep 13;277(37):33537-40
references.pmid: 12145273
references.citation: Trends Cell Biol. 1993 Jul;3(7):211-3
references.pmid: 14731754
references.citation: Trends Cell Biol. 2003 Feb;13(2):65-70
references.pmid: 12559756
references.citation: J Biol Chem. 1996 Oct 18;271(42):25928-35
references.pmid: 8824227
references.citation: Science. 1988 Apr 8;240(4849):210-3
references.pmid: 3281258
references.citation: J Biol Chem. 1999 Sep 24;274(39):27632-41
references.pmid: 10488103
references.citation: Exp Cell Res. 1998 Aug 1;242(2):548-60
references.pmid: 9683541
references.citation: J Biol Chem. 1993 Sep 15;268(26):19173-6
references.pmid: 7690027
references.citation: Prog Cell Cycle Res. 1995;1:9-19
references.pmid: 9552350
references.citation: J Biol Chem. 1997 Mar 14;272(11):7093-8
references.pmid: 9054402
references.citation: Prog Cell Cycle Res. 2003;5:19-30
references.pmid: 14593697
references.citation: Hum Mol Genet. 2003 Jul 15;12(14):1767-79
references.pmid: 12837699
references.citation: Cell Regul. 1990 Apr;1(5):435-43
references.pmid: 2099192
references.citation: Prog Cell Cycle Res. 2003;5:249-59
references.pmid: 14593719
references.citation: Am J Physiol. 1996 Jun;270(6 Pt 2):F960-70
references.pmid: 8764315
references.citation: BMC Mol Biol. 2001;2:12
references.pmid: 11696240
references.citation: Trends Biochem Sci. 1997 Dec;22(12):482-7
references.pmid: 9433129
references.citation: Thromb Res. 1995 Jan 1;77(1):55-61
references.pmid: 7701477
references.citation: Circulation. 1998 Jul 7;98(1):82-9
references.pmid: 9665064
references.citation: Arterioscler Thromb Vasc Biol. 2002 Sep 1;22(9):1439-44
references.pmid: 12231563
references.citation: Oncogene. 2001 Jul 12;20(31):4138-49
references.pmid: 11464280
references.citation: J Clin Invest. 1998 Mar 1;101(5):940-8
references.pmid: 9486962
references.citation: Nat Med. 1997 Feb;3(2):231-4
references.pmid: 9018245
references.citation: Mol Cell Biol. 2001 Aug;21(15):4960-7
references.pmid: 11438653
references.citation: J Biol Chem. 2002 Jan 18;277(3):2302-10
references.pmid: 11704659
references.citation: Curr Biol. 1999 Jun 17;9(12):661-4
references.pmid: 10375532
references.citation: Annu Rev Biochem. 1978;47:715-50
references.pmid: 354504
references.citation: J Cell Biochem. 2003 Oct 15;90(3):548-60
references.pmid: 14523989
references.citation: Cytometry. 1983 Mar;3(5):328-31
references.pmid: 6839881
references.citation: Circulation. 2000 Oct 24;102(17):2124-30
references.pmid: 11044431
references.citation: Nature. 1993 Apr 29;362(6423):801-9
references.pmid: 8479518
references.citation: Arterioscler Thromb Vasc Biol. 2001 Jul;21(7):1152-8
references.pmid: 11451744