Regulation of the ras signalling network

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Abstract
The mitogenic action of cytokines such as epidermal growth factor (EGF)d̊ or platelet dericed growth factor (PDGF) involves the stimulation of a signal cascade controlled by a small G protein called Ras. Mutations of Ras can cause its constitutive activation and, as a consequence, bypass the regulation of cell growth by cytokines. Both growth factor‐induced and oncogenic activation of Ras involve the conversion of Ras from the GDP‐bound (D‐Ras) to the GTP‐bound (T‐Ras) forms. T‐Ras activates a network of protein kinases including c‐Mos, c‐Raf‐1 and MAP kinase. Eventually the activation of MAP kinase leads to the activation of the elongation factor 4E and several transcription factors such as c‐Jun, c‐Myc and c‐Fos. There are several modulators of Ras activity, such as the GTPase activating proteins (GAP1 and NF1), which stimulate the coversion of T‐Ras to D‐Ras. A series of small NF1 fragments, which bind T‐Ras, as well as truncated forms or derivatives of c‐Raf‐1, c‐Jun and c‐Myc, are capable of blocking the T‐Ras‐activated mitogenesis in a competitive manner. These agents offer a unique opportunity to control the proliferation of T‐Ras‐associated tumors, which represent more than 30% of total human carcinomas.