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1 Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
2 Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
3 Medicine, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA; Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: balkovet{at}uab.edu.
Increasing cell density arrests epithelial cell proliferation by a process termed contact inhibition. We investigated mechanisms of contact inhibition using a model of contact inhibited epithelial cells. Hepatocyte growth factor (HGF) treatment of contact-inhibited MDCK cells stimulated cell proliferation and increased levels of phosphorylated ERK 1/2 (phospho-ERK 1/2) and cyclin D1. MEK inhibitors, PD98059 and UO126, inhibited these HGF-dependent changes indicating the dependence on phosphorylation of ERK 1/2 during HGF-induced loss of contact inhibition. In relation to contact inhibited high-density cells, low-density MDCK cells proliferate and had higher levels of phospho-ERK 1/2 and cyclin D1. PD98059 and UO126 inhibited low-density MDCK cell proliferation. Trypsinization of high-density MDCK cells immediately increased phospho-ERK 1/2 and was followed by a transient increase in cyclin D1 levels. Reformation of cell junctions after trypsinization led to decreases in phospho-ERK 1/2 and cyclin D1 levels. High-density MDCK cells express low levels of both cyclin D1 and phospho-ERK 1/2 and treatment of these cells with fresh medium containing HGF but not fresh medium alone for 6 h increased phospho-ERK 1/2 and cyclin D1 levels as compared to cells without medium change. These data provide evidence that HGF abrogates MDCK cell contact inhibition by increasing ERK 1/2 phosphorylation and levels of cyclin D1. These results suggest that in MDCK cells contact inhibition of cell proliferation in the presence of serum occurs by cell density dependent regulation of ERK 1/2 phosphorylation.
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