Proto-oncogene Overexpression

Roy, H.K., Olusola, B.F., Clemens, D.L. et al. 2002. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 23 201-305. 

The cellular form of oncogenes (known as c-oncogenes or proto-oncogenes) code for proteins involved in controlling growth and differentiation processes. They only become oncogenes if their sequence has been altered by mutations (see p. 256), deletions, and other processes, or when excessive amounts of the gene products have been produced as a result of overexpression. 

Hydrogen peroxide transformed mouse myeloid progenitor cells (FDC-Pl) from interleukin-3 dependence to factor independence, but only at cytotoxic concentrations (> 12/5 pmol/L). Such a transformation was not induced by non-specific insults to the cells, such as sodium fluoride or heat shock treatment. The transformed cells produced tumours when injected into pre-irradiated mice (Crawford Greenberger, 1991). Hydrogen peroxide (10 pmol/L) induced overexpression of the proto-oncogene c-jun in hamster tracheal epithelial (HTE) cells c-jun overexpression led to proliferation and increased growth rate, as well as increased anchorage-independence of HTE cells (Timblin et al., 1995). 

Since many cellular oncogenes were originally identified in transforming retroviruses, and since some retroviruses cause rapid malignant transformation in animals, notably chicken, it seemed for a while that most human cancers are caused by infection with retroviruses. But that is not the case. The number of human cancers which originate from retroviral infections is actually rather small (Table 15.2). In many cases, proto-oncogenes can become oncogenes by mutation or overexpression in human cells, without retroviral assistance. 

Every proto-oncogene encoding a normal constituent of a signalling pathway can become an oncogene when mutated or overexpressed. Only a few examples are given, because the properties and functions of the normal cellular proteins encoded by proto-oncogenes... 

The mitochondrial control of cell fate in vertebrates involves interactions among proteins of the B cell lymphoma-2 (Bcl-2) proto-oncogene family, which has been functionally conserved throughout metazoan evolution. Its involvement in programmed cell death was first described in Caenorhabditis elegans, where it was shown that expression of ced-4 was required for cell death activation, whereas ced-9 overexpression maintained cell viability by suppressing interactions between the products of ced-4 and downstream cell death executioner proteins109. 

PRADl/Bcl-1 is a proto-oncogene first discovered in the PTH gene in a subset of parathyroid adenomas. It belongs to the cyclin family of proteins and resides on chromosome llql3. The overexpression of its protein has been demonstrated in several epithelial tumors. Expression is more limited in lymphomas, particularly mantle cell lymphoma (Fig. 6.8), hairy cell leukemia, and a subset of multiple myeloma. Mantle cell lymphoma is characterized by a t (Il 14)(ql3 q32) translocation. 

Although the exact mechanism responsible for the proapoptotic effects of capsaicin remains unknown, several different mechanisms have been proposed, including the inhibition of plasma membrane nicotinamide adenine dinucleotide reduced (NADH) oxidase activity [121], regulation by Bcl-2 and calcineurin [122], and the overexpression of the p53 tumor suppressor gene and/or c-myc proto-oncogene [123]. Since tumor promotion is related to inflammation, the anti-inflammatory and anti-tumoral effects of capsaicin are most likely directly related to each other and are thus both of interest. In addition, the activation of NF-kB by... 

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