H-ras gene

Cha RS, Zarbl H, Keohavong P, Thilly WG (1992) Mismatch amplification mutation assay (MAMA) Application to the c-H-ras gene. PCR Methods Appl 2 14-20. 

D. Chakravarti, P. C. Mailander, K.-M. Li, S. Higginbotham, and H. L. Zhang, Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene. Oncogene 20 (2001), 7945-7953. 

The role of depurinating adducts and apurinic sites in the PAH-induced cancer process is controversial and has yet to be fully elucidated. There are lines of evidence that both support and refute this theory. In support of this theory, the levels of depurinating adducts of B[a]P correlated with mutations in the H-ras oncogene in DNA isolated from mouse skin papillomas initiated by this compound (Chakravarti et al. 1995). It is well known that the initiation of skin tumors in mice is associated with the formation of mutations in the H-ras gene [reviewed by Ross and Nesnow (1999)]. DB[a,/]P treatment of mouse skin forms papillomas which contain the H-ras codon 61 (CAA to CTA) mutation. These same mutations were induced in early preneoplastic skin within one day after DB[a,/]P treatment and appear to be related to DB[a,/]P-Ade-depurinating adducts. Studies have shown that apurinic... 

The frequency of active ras oncogenes in human bladder cancer (F6) associated with schistosomiasis was examined. Of nine squamous cell carcinomas of the bladder, none scored as positive in the regular DNA transfection assay. The restriction fragment polymorphism assay at codon 12 of the H-ras gene confirmed the absence of an activating mutation at this site in all samples. Western blotting analyses of the ras p21 proteins suggested a point mutation with codon 61 in one sample only. Enhanced expression of the ras p21 protein was demonstrated in four samples. 

Salto S, Hata M, Fukuyama R, Sakai K, Kudoh J, Tazaki H, Shimizu N. Screening of H-ras gene point mutations in 50 cases of bladder carcinoma. Int J Urol 1997 4 178-185. 

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. 

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). 

In many chronic inflammatory diseases, angiogenesis can be identified in the inflamed lesions. For example, in rheumatoid arthritis extensive neovascularization is present in the inflamed synovium where it is one of the earliest histopathological findings [36]. Since in RA synoviocytes exhibit characteristics of tumour cells, including somatic mutations in key regulatory genes such as H-ras and the p53 tumour suppressor, RA can be viewed as a multicentric tumour-like mass that invades and destroys its local environment [37]. Concurrent increased endothelial cell turnover may contribute to microvascular dysfunction and thereby facilitate persistent synovitis. 

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. 

Members of the myc gene family have been implicated in the control of normal cell proliferation as well as in neoplasia. A more direct role for myc genes in transformation is indicated by their ability to transform primary rat embryo fibroblasts in association with the c-H-ras oncogene. 

Ras genes are frequently mutated in chemically induced animal tumors and are the most frequently detected mutated oncogenes in human tumors. Approximately 20-30% of all human tumors contain mutated ras. The Ras subfamily includes H-ras, K-ras, and N-ra.v, and all have been found to be mutationally activated in numerous types of tumors from a large variety of species including humans. 

The authors thank Dr. Antonios Makris for providing the cDNA encoding the human H-Ras and Raf-1 genes. We also thank Dr. Alan Hinnebusch for providing the pNKY51 plasmid. EG was supported by NIH core grant CA-06927, and an appropriation from the Commonwealth of Pennsylvania (to Fox Chase Cancer Center). 

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