Three-dimensional matrix suppresses E2F-controlled gene expression in glomerular mesangial cells.

Abstract

BACKGROUND: Extracellular matrix (ECM) regulates mitogenesis of glomerular mesangial cells. Currently, however, the molecular mechanisms that mediate the control of cell growth by ECM are not fully elucidated. METHODS: The effects of structurally distinct forms of type I collagen matrix on mesangial cell proliferation and cell cycle distribution were examined. Expressions of the cell cycle-regulatory transcription factor E2F and retinoblastoma susceptibility gene family proteins were also investigated. RESULTS: Mesangial cells cultured on monomeric collagen matrix showed a substantial growth response to serum. In contrast, mesangial cells cultured on polymerized collagen matrix exhibited arrest of the cell cycle in the G0/G1 phase. The induction of the quiescent phenotype was correlated with down-regulation of E2F-1, the prototypal transcription factor that controls cell cycle progression. The suppression of E2F-1 was associated with (1) dephosphorylation of retinoblastoma susceptibility gene proteins, pRB and p130, and (2) accumulation of E2F-pRB and E2F-p130 DNA binding complexes that bind to the E2F consensus sequence located in the E2F-1 promoter. Other E2F regulatory genes, including c-myc, cyclin A, and cdc 2, were also down-regulated in mesangial cells cultured on polymerized collagen matrix. CONCLUSION: These results suggest that a three-dimensional collagen induces cell cycle arrest via suppression of E2F-controlled gene expression in mesangial cells. Dephosphorylation of pRB and p130 and subsequent generation of transrepressor complexes, E2F-pRB and E2F-p130, may be involved in this process.