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Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin
J A Varner1, D A Emerson, R L Juliano
1Department of Pharmacology, University of North Carolina, Chapel Hill 27599, USA.
Abstract:
Cells selected for overexpression of the integrin alpha 5 beta 1 show decreased proliferation and loss of the transformed phenotype. We provide evidence that de novo expression of the integrin alpha 5 beta 1 in HT29 colon carcinoma cells results in the growth arrest of these cells as characterized by reduced DNA synthesis and cellular proliferation in vitro. In fact, expression of integrin alpha 5 beta 1 on these cells induces the transcription of growth arrest specific gene 1 (gas-1), a gene product known to induce cellular quiescence, but blocks transcription of the immediate early genes c-fos, c-jun, and jun B. In vivo, the alpha 5 beta 1 transfectants display dramatically reduced tumorigenicity as well as a highly differentiated phenotype when compared with their pSVneo-transfected counterparts. Surprisingly, ligation of alpha 5 beta 1 on these cells by cell attachment to a fibronectin substrate not only reverses the growth inhibition and gas-1 gene induction but activates immediate early gene transcription. These findings demonstrate that integrin alpha 5 beta 1 expression in the absence of attachment to fibronectin activates a signaling pathway leading to decreased cellular proliferation and that ligation of this receptor with fibronectin reverses this signal, thereby contributing to the proliferation of transformed cells.
Insights
Overexpression of integrin alpha 5 beta 1 in colon cancer cells halts growth and differentiation. Fibronectin binding reverses this effect, suggesting a role in transformed cell proliferation.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Integrins are cell surface receptors crucial for cell adhesion and signaling.
- Integrin alpha 5 beta 1 plays roles in cell growth, differentiation, and cancer progression.
- HT29 colon carcinoma cells are a model system for studying colorectal cancer.
Purpose of the Study:
- To investigate the role of de novo integrin alpha 5 beta 1 expression in HT29 colon carcinoma cell proliferation and phenotype.
- To elucidate the signaling pathways involved in integrin alpha 5 beta 1-mediated growth arrest and reversal.
Main Methods:
- Overexpression of integrin alpha 5 beta 1 in HT29 colon carcinoma cells.
- Assessment of cellular proliferation, DNA synthesis, and gene transcription (gas-1, c-fos, c-jun, jun B).
- In vivo tumorigenicity assays and phenotypic analysis.
- Cell attachment assays to fibronectin substrate and subsequent signaling analysis.
Main Results:
- De novo integrin alpha 5 beta 1 expression induced growth arrest, reduced proliferation, and increased gas-1 transcription.
- Integrin alpha 5 beta 1 overexpression blocked immediate early gene transcription (c-fos, c-jun, jun B).
- In vivo, alpha 5 beta 1 transfectants showed reduced tumorigenicity and a differentiated phenotype.
- Fibronectin ligation reversed growth inhibition and gas-1 induction, activating immediate early gene transcription.
Conclusions:
- Integrin alpha 5 beta 1 signaling, independent of fibronectin, inhibits colon carcinoma cell proliferation and promotes differentiation.
- Fibronectin binding to alpha 5 beta 1 activates signaling pathways that promote proliferation in transformed cells.
- Integrin alpha 5 beta 1 is a key regulator of colon cancer cell behavior, with its function modulated by extracellular matrix interactions.