Apoptosis, induction cell mutation

Herman-Antosiewicz A and Singh S V (2004), Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds a review , Mutation Res, 555, 121-131. 

Chakraborty S, Ghosh U, Bhattacharyya NP, Bhattacharya RK, Roy M. 2006. Inhibition of telomerase activity and induction of apoptosis by curcumin in K-562 cells. Mutat Res 596 81-90. 

HPV-16 encodes a set of early gene oncoproteins (E6 and E7) responsible for cellular immortalization. HPV types 16 and 18 E6 and E7 proteins are known to interact strongly with p53 and retinoblastoma (Rb) tumor suppressor gene products, respectively (2). The association of E6 with p53 marks this tumor suppressor for rapid ubiquitin-mediated proteolysis. Reduced levels of p53 prevent the cell from activating cell cycle arrest and/or induction of apoptosis in genetically mutated cells. 

This chapter focuses on the mechanisms responsible for the lower mutation frequency in mES cells. mES cells and somatic cells will be compared on basis of the extent of DNA damage, the cell cycle control mechanisms that are involved, the efficiency of the DNA repair and apoptosis induction. Furthermore mES cells have an additional mechanism to avoid passing on mutations to their progeny, i.e. induction of differentiation. A review of these issues in other embryonic stem cell types, more specifically hES cells and induced pluripotent stem cells, will be briefly discussed. Finally, the relation between these mES cell features and the in vivo situation will be described. 

The double edged sword effect of Cd ", namely apoptosis and cancer progression, is reflected in its opposing effects on p53. Cd " inhibits DNA base excision repair in p53-dependent and -independent manners [593], increases p53 phosphorylation as a prelude to apoptosis [594,595], and arrests cells in G1 and G2/M checkpoints via p53-dependent [510] and -independent [596] mechanisms. Cd " can affect p53 in two ways p53 is activated by phosphorylation via phosphatidylinositol-3-kinase related kinases [479] or Cd replaces zinc to maintain its mutated non-DNA binding form preventing apoptosis induction [597]. 

Like sulforaphane, however, PEITC-NAC (N-acetylcysteine) conjugate appears to block in Gl. Studies by Lund et al. show that in the case of the colorectal cell line HT29, which lacks wild type p53, treatment with AITC causes the cells to detach from the substratum but, at least in the short-term, they do not then enter apoptosis . Where it does occur, induction of apoptosis by isothiocyanate appears to be a p53-dependent process. However, this statement must also be qualified, because the effect appears to depend on which metabolite is considered. For example, sulforaphane does appear to be able to induce apoptosis in HT29 cells, which express a mutated form of the protein. 

The p53 protein is essential for the induction of apoptosis as a response to chromosomal damage (e.g., y-irradiation). It acts by blocking DNA replication of damaged cells. Cells deficient in p53 replicate in spite of the DNA damage to accumulate further mutations, thereby producing effects similar to overexpression of Bcl-2 to favor the accumulation of further mutations and reduce the efficiency of drugs for chemotherapy (E2). 

Konopacka, M., Rzeszowska-Wolny, J. (2006). The bystander effect-induced formation of micronucleated cells is inhibited by antioxidants, hut the parallel induction of apoptosis and loss of viability are not affected. Mutat. Res. 593 32-8. 

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