Ha-ras gene

Spalding, J.W., Momma, J., Elwell, M.R. Tennant, R.W. (1993) Chemically induced skin carcinogenesis in a transgenic mouse line (TG-AC) carrying a v-Ha-ras gene. Carcinogenesis, 14, 1335-1341... 

Koizumi, M. and Ohtsuka, E. (1992) Design of RNAs that inhibit the activated c-Ha-ras gene in mammalian cells. Ann. N.Y. Acad. Sci., 660, 276. 

Yamamoto S, Urano K, Nomura T. Validation of transgenic mice harboring the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Toxicology Letts 1998 102-3 473-8. 

Brown, K., A. Buchmann and A. Balmain. Carcinogen-induced mutations in the mouse c-Ha-ras gene provide evidence of multiple pathways for tumour progression. Proc. Natl. Acad. Sci. USA 87 538-542, 1990. 

Nelson, M. A., Eutscher, B. W., Kinsella, T., Wymer, J., and Bowden, G. T. (1992). Detection of mutant Ha-ras genes in chemically initiated mouse skin epidermis before the development of benign tumors. 

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. 

In animal studies, mirex (a nonmutagenic hepatocarcinogen) promoted mouse skin squamous carcinomas and papillomas after initiation with 7,12-dimethyl-benz[a]anthracene (DMBA) for 1 week. Mirex, also, potentiated the promotional potency of the phorbol ester tumor promoter, 12-0 -tetradecanoylphorbol-13-acetate (TPA). There was a 90% incidence (activation) of the c-Ha-ras tumor gene in these co-promoted tumors. When both mirex and TPA gave a similar tumor yield, only the TPA response was associated with biochemical markers of enhanced cell proliferation, induction of epidermal ornithine decarboxylase activity and increased DNA synthesis, and hyperplasia. Thus, there is evidence for a dual effect of mirex during co-promotion first, as an independent tumor promoter with a mechanism different than that of phorbol esters and second, as a compound that also potentiates skin tumor promotion by TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). 

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. 

Levine, A.E. Chakrabarty, S. (1992) Response of FR3T3 cells transformed by Ha-ras oncogene and epidermal growth factor gene to differentiation induction by A A -dimethylformamide. Int. J. Cancer, 50, 653-658... 

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