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  • Original Article
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TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

Oncogene volume 25, pages 3041–3048 (2006)Cite this article

Abstract

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 G1. TIMP-1-mediated cell cycle arrest is associated with its downregulation of cyclin D1 and upregulation of p27KIP1, 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 D1 and p27KIP1 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 D1 and p27KIP1 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.

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Abbreviations

TIMP:

Tissue inhibitor of metalloproteinase

MMP:

matrix metalloproteinase

ECM:

extracellular matrix

CDKI:

cyclin-dependent kinase inhibitor

Rb:

retinoblastoma

ADAM:

a disintegrin and a metalloproteinase domain

AS:

antisense

mAb:

monoclonal antibody

pAb:

polyclonal antibody

rTIMP:

recombinant tissue inhibitor of metalloproteinase

FAK:

focal adhesion kinase

PI3-K:

phosphatidylinositol 3-kinase

ERKs:

extracellular signal-regulated kinases

EPA:

erythroid-potentiating activity

polyHEMA:

polyhydroxyethylmethacrylate

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Acknowledgements

This work is supported by NIH/National Cancer Institute Grant CA89113 (to H-R CK).

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  1. Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    M E Taube, X-W Liu, R Fridman & H-R C Kim

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  1. M E Taube
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Correspondence to H-R C Kim.

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Taube, M., Liu, XW., Fridman, R. et al. TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein. Oncogene 25, 3041–3048 (2006). https://doi.org/10.1038/sj.onc.1209336

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