TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27(KIP1) protein.
Increasing evidence suggests that tissue inhibitor of metalloproteinases-1 (TIMP-1) can directly regulate cell growth and apoptosis independent of its matrix metalloproteinases (MMPs)-inhibitory activity. While TIMP-1's antiapoptotic activity has been well demonstrated, conflicting data has been reported regarding TIMP-1's role in growth regulation. Here we show that TIMP-1 reduces the growth rate of human breast epithelial (MCF10A) cells by inducing cell cycle arrest at G(1). TIMP-1-mediated cell cycle arrest is associated with its downregulation of cyclin D(1) and upregulation of p27(KIP1), resulting in inhibition of cyclin-dependent kinase activity necessary for phosphorylation of the tumor suppressor retinoblastoma protein. We further show that TIMP-1 modulation of cyclin D(1) and p27(KIP1) is achieved through TIMP-1-mediated differential regulation of protein stability independent of growth factor signaling. We also show that TIMP-1-mediated differential regulation of cyclin D(1) and p27(KIP1) is independent of cell adhesion signaling. Whereas approximately 50% of MCF10A cells with reduced TIMP-1 expression underwent cell death following loss of cell adhesion (anoikis), TIMP-1 overexpressing cells remained viable with prominent cell cycle arrest without detectable cell death. Taken together, we propose that TIMP-1-mediated cell survival independent of cell adhesion is accompanied with cell cycle arrest in human breast epithelial cells, although cell cycle regulation may not be a prerequisite for TIMP-1 regulation of apoptosis in general.
Taube
M E
ME
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Liu
X-W
XW
Fridman
R
R
Kim
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HR
D001940:Breast / Q000166:cytology*; D002448:Cell Adhesion; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D019938:Cyclin D1 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003513:Cycloheximide / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007976:Leupeptins / Q000494:pharmacology; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology*
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D011480:Protease Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D019715:Tissue Inhibitor of Metalloproteinase-1; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003513:Cycloheximide; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde