Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappa B

Ral GTPases have been implicated as mediators of Ras-induced signal transdu ction from observations that Ral-specific guanine nucleotide exchange facto rs associate with Ras and are activated by Ras. The cellular role of Ral fa mily proteins is unclear, as is the contribution that Ral may make to Ras-d ependent signaling. Here we show that expression of activated Ral in quiesc ent rodent fibroblasts is sufficient to induce activation of NF-kappa B-dep endent gene expression and cyclin D1 transcription, two key convergence poi nts for mitogenic and survival signaling. The regulation of cyclin D1 trans cription by Ral is dependent on NF-kappa B activation and is mediated throu gh an NF-kappa B binding site in the cyclin D1 promoter. Ral activation of these responses is likely through an as yet uncharacterized effector pathwa y, as ne find activation of NF-kappa B and the cyclin D1 promoter by Ral is independent of association of Ral with active phospholipase D1 or Ral-bind ing protein 1, two proteins proposed to mediate Ral function in cells.