The p16INK4a tumour suppressor protein inhibits αvβ3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of αvβ3 to focal contacts

被引:101
作者
Fåhraeus, R [1 ]
Lane, DP [1 ]
机构
[1] Univ Dundee, Dept Biochem, CRC Labs, Dundee DD1 4HN, Scotland
关键词
alpha(v)beta(3) integrin; cancer; integrin regulatory pathway; p16(INK4a) tumour suppressor protein;
D O I
10.1093/emboj/18.8.2106
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Expression of full-length p16(INK4a) blocks alpha(v)beta(3) integrin-dependent cell spreading on vitronectin but not collagen IV. Similarly, G(1)-associated cell cycle kinases (CDK) inhibitory (CKI) synthetic peptides derived from p16(INK4a), p18(INK4c) and p21(Cip1/Waf1), which can be delivered directly into cells from the tissue culture medium, do not affect non-alpha(v)beta(3)-dependent spreading on collagen IV, laminin and fibronectin at concentrations that inhibit cell cycle progression in late G(1). The alpha(v)beta(3) heterodimer remains intact after CKI peptide treatment but is immediately dissociated from the focal adhesion contacts, Treatment with phorbol 12-myristate 13-acetate allows alpha(v)beta(3) to locate to the focal adhesion contacts and the cells to spread on vitronectin in the presence of CKI peptides, The cdk6 protein is found to suppress p16(INK4a)-mediated inhibition of spreading and is also shown to localize to the ruffling edge of spreading cells, indicating a function for cdk6 in controlling matrix-dependent cell spreading, These results demonstrate a novel G(1) CDK-associated integrin regulatory pathway that acts upstream of alpha(v)beta(3)-dependent activation of PKC as well as a novel function for the p16(INK4a) tumour suppressor protein in regulating matrix-dependent cell migration.
引用
收藏
页码:2106 / 2118
页数:13
相关论文
共 61 条
[1]  
Adams PD, 1996, MOL CELL BIOL, V16, P6623
[2]   Cell anchorage and the cytoskeleton as partners in growth factor dependent cell cycle progression [J].
Assoian, RK ;
Zhu, XY .
CURRENT OPINION IN CELL BIOLOGY, 1997, 9 (01) :93-98
[3]   BETA(1) INTEGRINS SIGNAL LIPID 2ND-MESSENGERS REQUIRED DURING CELL-ADHESION [J].
AUER, KL ;
JACOBSON, BS .
MOLECULAR BIOLOGY OF THE CELL, 1995, 6 (10) :1305-1313
[4]   Polyethylenimine (PEI) is a simple, inexpensive and effective reagent for condensing and linking plasmid DNA to adenovirus for gene delivery [J].
Baker, A ;
Saltik, M ;
Lehrmann, H ;
Killisch, I ;
Mautner, V ;
Lamm, G ;
Christofori, G ;
Cotten, M .
GENE THERAPY, 1997, 4 (08) :773-782
[5]   Cell-cycle arrest and inhibition of Cdk4 activity by small peptides based on the carboxy-terminal domain of p21(WAF1) [J].
Ball, KL ;
Lain, S ;
Fahraeus, R ;
Smythe, C ;
Lane, DP .
CURRENT BIOLOGY, 1997, 7 (01) :71-80
[6]   REQUIREMENT OF VASCULAR INTEGRIN ALPHA(V)BETA(3) FOR ANGIOGENESIS [J].
BROOKS, PC ;
CLARK, RAF ;
CHERESH, DA .
SCIENCE, 1994, 264 (5158) :569-571
[7]   Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3 [J].
Brooks, PC ;
Stromblad, S ;
Sanders, LC ;
vonSchalscha, TL ;
Aimes, RT ;
StetlerStevenson, WG ;
Quigley, JP ;
Cheresh, DA .
CELL, 1996, 85 (05) :683-693
[8]  
CHAN FKM, 1995, MOL CELL BIOL, V15, P2682
[10]   Adenovirus-mediated p16/CDKN2 gene transfer suppresses glioma invasion in vitro [J].
Chintala, SK ;
Fueyo, J ;
GomezManzano, C ;
Venkaiah, B ;
Bjerkvig, R ;
Yung, WKA ;
Sawaya, R ;
Kyritsis, AP ;
Rao, JS .
ONCOGENE, 1997, 15 (17) :2049-2057