Genes, ras

Shvedova et al. [59] demonstrated that inhalation of SWNTs resulted in mutations of the k-ras gene locus in the lung of mice. Among the mutated genes implicated in pulmonary tumorigenesis, the k-ras oncogene is relevant in lung tumors of mice exposed to chemicals. 

Ch. 25). This means that mutations in these proteins that result in alterations in their regulatory properties can lead to oncogenesis. Ras in particular has been implicated in several human cancers [32]. It has been estimated that as many as 30% of all human cancers contain mutations in one of the three Ras genes. While the frequency of Ras mutations in some types of human cancer is very low, its frequency in certain cancers, such as squamous cell carcinoma, lymphatic cancers and colorectal adenocarcinoma, is very high. 

Toxicity and effectivity studies have often been performed in rodent fibroblast cells containing oncogenic H-Ras. However, prenylation of K-Ras B and N-Ras are not as effectively blocked by the farnesyltransferase inhibitors as H-Ras [48] (see below). Thus normal cells may be less sensitive to these drugs because they express K-Ras 4B and N-Ras. In this context it should be noted that H-Ras mutations are relatively uncommon in human tumors [49]. Rather, the K-Ras gene is the most frequently mutated in solid human cancers, whereas N-Ras is prevalent in leukemias. Thus the preclinical evaluation of the farnesylation inhibitors has yet to be critically re-evaluated for trials in humans. 

Inhibition of the lipid modification cascade provides an alternative way to block aberrant signaling pathways and that opportunity can be exploited in anticancer therapy. As part of the growth factor, signaling of the false activation is transmitted by the mutated ras gene encoded proteins (Ras) and ultimately leads to uncontrolled cell growth. These typical GTP binding proteins are also subject to membrane anchoring and the biosynthesis of those Ras proteins can be blocked at the posttranslational prenylation step. 

Stimulation of the monomeric G protein (p21 ) encoded by the normal ras gene... 

Boissel, N., Leroy, H., Brethon, B., Philippe, N., de Botton, S., Auvrignon, A., Raffoirx, E., Leblanc, T., Thomas, X., Hermine, 0., et al. (2006) Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBE AML). 

Ras, a historical proto-oncogene, is frequently mutated in many human cancers, including 90% of pancreatic cancers, 50% of colorectal cancers, 30% of lung cancers, and 15-30% of melanomas [10-12]. There are three Ras genes that encode four family members K-Ras (two alternatively spliced isoforms), H-Ras, and N-Ras. Mutations are most commonly found in K-Ras [13]. These mutations result in impaired GTP hydrolysis, which shifts the equilibrium toward GTP-bound active Ras, and results in constitutive intracellular signaling. 

Jackson EL, Willis N, Mercer K et al (2001) Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 15 3243-3248... 

The general importance of Ras proteins in growth regulation was recognized at the beginning of the 1980s, when it was demonstrated that close to 30 % of all solid tumors in humans show a mutation in the Ras gene. 

The transition from inactive GDP state to active GTP state may be accelerated by proteins that cause the boimd GDP to dissociate. The guanine nucleotide exchange factors (GEF) play an essential role in signal transduction via Ras proteins. Loss of exchange activity by mutation of the exchange proteins has the same effect in lower organisms as loss of the Ras gene. 

Balmain, A., Ramsden, M., Bowden, G., and Smith, J. (1984). Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas, Nature 307,658. 

Lamb RA. Genes and proteins of the influenza virus. In Krug RM, ed. The Influenza Viruses, ed. New York Plenum, 1989 1-87. 

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