The cyclopentenone 15-deoxy-⌬ 12,14 -prostaglandin J2 (15d-PGJ2) induces cell proliferation and mitogen-activated protein kinase activation. Here, we describe that these effects are mediated by 15d-PGJ 2-elicited H-Ras activation. We demonstrate that this pathway is specific for H-Ras through the formation of a covalent adduct of 15d-PGJ 2 with Cys-184 of H-Ras, but not with N-Ras or K-Ras. Mutation of C184 inhibited H-Ras modification and activation by 15d-PGJ 2, whereas serum-elicited stimulation was not affected. These results describe a mechanism for the activation of the Ras signaling pathway, which results from the chemical modification of H-Ras by formation of a covalent adduct with cyclopentenone prostaglandins.mitogen-activated protein kinase ͉ cell proliferation ͉ posttranslational modification
Although protein kinase C (PKC) has been widely implicated in the positive and negative control of proliferation, the underlying cell cycle mechanisms regulated by individual PKC isozymes are only partially understood. In this report, we show that PKC␦ mediates phorbol ester-induced G 1 arrest in lung adenocarcinoma cells and establish an essential role for this novel PKC in controlling the expression of the cell cycle inhibitor p21. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) in early G 1 phase impaired progression of lung adenocarcinoma cells into S phase, an effect that was completely abolished by specific depletion of PKC␦, but not PKC␣. Although the PKC effect was unrelated to the inhibition of cyclin D1 expression, PKC activation significantly up-regulated p21 and down-regulated Rb hyperphosphorylation and cyclin A expression. Elevations in p21 mRNA and protein by PMA were mediated by PKC␦ but not PKC␣. Studies using luciferase reporters also revealed an essential role for PKC␦ in the PMA-induced inhibition of Rb-dependent cyclin A promoter activity. Finally, we showed that the cell cycle inhibitory effect of PKC␦ is greatly attenuated by RNA interference-mediated knock-down of p21. Our results identify a novel link between PKC␦ and G 1 arrest via p21 up-regulation and highlight the complexities in the downstream effectors of PKC isozymes in the context of cell cycle progression and proliferation.
The Son of Sevenless (Sos) factors were originally discovered 2 decades ago as specialized Ras activators in signaling pathways controlling the process of R7 cell development in the eye of Drosophila melanogaster. The 2 known members of the mammalian Sos family (Sos1 and Sos2) code for ubiquitously expressed, highly homologous (69% overall) proteins involved in coupling signals originated by cell surface receptor tyrosine kinases (RTKs) to downstream, Ras-dependent mitogenic signaling pathways. Mechanistically, the Sos proteins function as enzymatic factors interacting with Ras proteins in response to upstream stimuli to promote guanine nucleotide exchange (GDP/GTP) and subsequent formation of the active Ras-GTP complex. In this review, we summarize current knowledge on structural, regulatory, and functional aspects of the Sos family, focusing on specific aspects of Sos biology such as structure-function relationship, crosstalk with different signaling pathways, and in vivo functional significance as deduced from phenotypic characterization of Sos knockout mice and human genetic syndromes caused by germline hSos1 mutations.
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