Mutational analysis of cell cycle inhibition by integrin β(1C)

Jere E. Meredith, William B. Kiosses, Yoshikazu Takada, Martin Alexander Schwartz

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19 Citations (Scopus)

Abstract

Integrin β(1C) is an alternatively spliced cytoplasmic variant of the β1 subunit that potently inhibits cell cycle progression. In this study, we analyzed the requirements for growth suppression by β(1C). A chimera containing the extracellular/transmembrane domain of the Tac subunit of the human interleukin 2 receptor (gp55) fused to the cytoplasmic domain of β(1C) (residues 732-805) strongly inhibited growth in mouse 10T1/2 cells even at low expression levels, whereas chimeras containing the β(1A), β(1B), β(1D), β3, and β5 cytoplasmic domains had weak and variable effects. The β(1C) cytoplasmic domain is composed of a membrane proximal region (732- 757) common to all β1 variants and a COOH-terminal 48-amino acid domain (758-805) unique to β(1C) The β(1C)-specific domain (758-805) was sufficient to block cell growth even when expressed as a soluble cytoplasmic green fluorescent protein fusion protein. These results indicate that growth inhibition by β(1C) does not require the intact receptor and can function in the absence of membrane targeting. Analysis of deletions within the β(1C)- specific domain showed that the 18-amino acid sequence 775-792 is both necessary and sufficient for maximal growth inhibition, although the 13 COOH- terminal residues (793-805) also had weak activity. Finally, β(1C) is known to be induced in endothelial cells in response to tumor necrosis factor and is down-regulated in prostate epithelial cells after transformation. The green fluorescent protein/β(1C) (758-805) chimera blocked growth in the human endothelial cell line EV304 and in the transformed prostate epithelial cell line DU145, consistent with a role for β(1C) as a growth inhibitor in vivo.

Original languageEnglish
Pages (from-to)8111-8116
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number12
DOIs
Publication statusPublished - Mar 19 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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  • Cite this

    Meredith, J. E., Kiosses, W. B., Takada, Y., & Schwartz, M. A. (1999). Mutational analysis of cell cycle inhibition by integrin β(1C). Journal of Biological Chemistry, 274(12), 8111-8116. https://doi.org/10.1074/jbc.274.12.8111