Regulation of the Ras signalling network.
The mitogenic action of cytokines such as epidermal growth factor (EGF) or platelet derived 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 conversion of T-Ras to D-Ras. A series of small NF1 fragments, which bind T-Ras, as well as truncated forms of 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.
Maruta
H
H
Ludwig Institute for Cancer Research, Melbourne, Australia.
Burgess
A W
AW
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
D016207:Cytokines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; D018631:ras Proteins