Suppressor gene inactivation

The types of studies mentioned here represent a new concept for suppressor gene inactivation during a preneoplastic stage progressing toward malignancy. 

DNA breakage, mutation, oncogene activation, tumour suppressor gene inactivation... 

Nucleic acids in the DNA contain a high number of nucleophilic sites that can be attacked by electrophilic intermediates (metabolites) of chemical compounds. DNA adducts formed may cause alterations in the expression of a critical gene in the cell and thus lead to cell death. For example, modification of p53 tumor suppressor gene may inactivate the functions of the p53 protein and render cells sensitive to malignant transformation. Also, formation of RNA adducts may inhibit key cellular events because RNA is essential for protein synthesis. 

Tumor suppressor genes Genes that normally restrain cell growth, but when missing or inactivated by mutation, allow cells to grow uncontrolled and tumors to form. 

Sequential mutations within colonic epithelium result in cellular replication or enhanced invasiveness. Genetic changes include mutational activation of oncogenes and inactivation of tumor suppressor genes. 

It is reported that various kinds of human tumor cells loose or alter the RIZl expression, and inactivation of mouse Rizl induces B cell lymphoma suggesting that RIZl acts as a tumor suppressor gene (reviewed by Canote et ai, 2002. Structures of the described H3K9 HLMTases are shown in Fig. 1... 

DNA repair may not occur properly when certain tumor suppressor genes have been inactivated through mutation or deletion ... 

The Rb locus that is affected by the mutation, and that causes retinoblastoma, is a tumour suppressor gene. It encodes the Rb protein which is an inhibitor of transcription. The Rb protein controls the expression of three genes, which are essential for cell proliferation by forming a complex with, and thus inactivating, a transcription factor for these genes. These are ... 

Recessive, loss-of-fimction mutations that delete or inactivate tumor suppressor genes alleviate controls on cell proliferation and survival. 

Mutated, inactivated tumor suppressor genes can be inherited through the germline from one person to another. 

The first mutation in a tumor suppressor gene such as BRCAl may be either inherited via the germline or sporadic (due to a random event in that person) and then the normal allele is somehow inactivated (see loss of heterozygosity below). 

Multiple mutations that activate oncogenes or inactivate tumor suppressor genes accumulate due to progressive loss of DNA repair mechanisms and cell cycle control. 

B. Loss or inactivation of tumor suppressor genes may lead to cancer. 

Tumor suppressor genes are genes that, by their inactivation due to mutations or deletion, promote tumor formation. The proteins for which they code are known as tumor suppressor proteins. Many of the known tumor suppressor proteins have a suppressing and negatively regulating effect on processes that are either directly associated with regulation of cell division or influence this in an indirect way. Other, equally important functions of tumor suppressor proteins are in the areas of DNA repair and cell adhesion. Inactivation of tumor suppressor genes can have various consequences ... 

A selection of other tumor suppressor genes is summarized in Table 14.2. Interestingly, an enzyme of phosphatidyl-inositol metabolism has been also identified as a tumor suppressor. The PTEN tumor suppressor gene codes for a phospholipid phosphatase which specifically cleaves a phosphate from the second messenger phosphatidyl-inosi-tol-3,4,5-trisphosphate (PtdInsPj, see 6.6.2). and thus inactivates the messenger (review Maehama and Dixon, 1999). ... 

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