alpha 5 beta 1 integrin controls cyclin D1 expression by sustaining mitogen-activated protein kinase activity in growth factor-treated cells

Cyclin D1 expression is jointly regulated by growth factors and cell adhesi on to the extracellular matrix in many cell types. Growth factors are thoug ht to regulate cyclin D1 expression because they stimulate sustained extrac ellular signal-regulated kinase (ERK) activity. However, we show here that growth factors induce transient ERK activity when added to suspended fibrob lasts and sustained ERK activity only when added to adherent fibroblasts. C ell attachment to fibronectin or anti-alpha 5 beta 1 integrin is sufficient to sustain the ERK signal and to induce cyclin D1 in growth factor-treated cells. Moreover, when we force the sustained activation of ERK, by conditi onal expression of a constitutively active MAP kinase/ERK kinase, we overco me the adhesion requirement for expression of cyclin D1. Thus, at least in part, fibroblasts are mitogen and anchorage dependent, because integrin act ion allows for a sustained ERK signal and the expression of cyclin D1 in gr owth factor-treated cells.