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PMID: 12052868 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Cell attachment to the extracellular matrix induces proteasomal degradation of p21(CIP1) via Cdc42/Rac1 signaling.

Molecular and cellular biology ·Vol. 22 ·No. 13 ·2002-07-00 ·Pages 4587-97

Bao W, Thullberg M, Zhang H, Onischenko A, Strömblad S

Abstract

The cyclin-dependent kinase 2 (Cdk2) inhibitors p21(CIP1) and p27(KIP1) are negatively regulated by anchorage during cell proliferation, but it is unclear how integrin signaling may affect these Cdk2 inhibitors. Here, we demonstrate that integrin ligation led to rapid reduction of p21(CIP1) and p27(KIP1) protein levels in three distinct cell types upon attachment to various extracellular matrix (ECM) proteins, including fibronectin (FN), or to immobilized agonistic anti-integrin monoclonal antibodies. Cell attachment to FN did not rapidly influence p21(CIP1) mRNA levels, while the protein stability of p21(CIP1) was decreased. Importantly, the down-regulation of p21(CIP1) and p27(KIP1) was completely blocked by three distinct proteasome inhibitors, demonstrating that integrin ligation induced proteasomal degradation of these Cdk2 inhibitors. Interestingly, ECM-induced proteasomal proteolysis of a ubiquitination-deficient p21(CIP1) mutant (p21K6R) also occurred, showing that the proteasomal degradation of p21(CIP1) was ubiquitin independent. Concomitant with our finding that the small GTPases Cdc42 and Rac1 were activated by attachment to FN, constitutively active (ca) Cdc42 and ca Rac1 promoted down-regulation of p21(CIP1). However, dominant negative (dn) Cdc42 and dn Rac1 mutants blocked the anchorage-induced degradation of p21(CIP1), suggesting that an integrin-induced Cdc42/Rac1 signaling pathway activates proteasomal degradation of p21(CIP1). Our results indicate that integrin-regulated proteasomal proteolysis might contribute to anchorage-dependent cell cycle control.

MeSH Terms
Acetylcysteine/analogs & derivatives,pharmacology Animals Cell Adhesion Cell Cycle Proteins/metabolism Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinase Inhibitor p27 Cyclins/genetics,metabolism Cysteine Endopeptidases/metabolism Cysteine Proteinase Inhibitors/pharmacology Down-Regulation Extracellular Matrix/metabolism Fibronectins/metabolism Humans Integrins/immunology,metabolism Mice Mitogen-Activated Protein Kinases/metabolism Multienzyme Complexes/antagonists & inhibitors,metabolism Mutation Proteasome Endopeptidase Complex Signal Transduction Tumor Suppressor Proteins/metabolism Ubiquitin/metabolism cdc42 GTP-Binding Protein/metabolism rac1 GTP-Binding Protein/metabolism
Chemicals
CDKN1A protein, human Cdkn1a protein, mouse Cdkn1b protein, mouse Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p21 Cyclins Cysteine Proteinase Inhibitors Fibronectins Integrins Multienzyme Complexes Tumor Suppressor Proteins Ubiquitin lactacystin Cyclin-Dependent Kinase Inhibitor p27 Mitogen-Activated Protein Kinases Cysteine Endopeptidases Proteasome Endopeptidase Complex cdc42 GTP-Binding Protein rac1 GTP-Binding Protein Acetylcysteine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Bao Wenjie
Karolinska Institutet, Department of Microbiology, Pathology and Immunology, Division of Pathology, Huddinge University Hospital, Stockholm, Sweden.
Thullberg Minna
Zhang Hongquan
Onischenko Anatoli
Strömblad Staffan
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.13.4587-4597.2002
Published
2002-07-00
Pages
4587-97
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC133897
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.22.13.4587-4597.2002 PMC Full Text View journal details
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