Ras And Genomic Instability

One of the consequences of Ras mutations in human tumors is destabilization of the karyotype. Expression of activated Ras in a variety of established cell lines and tumor cells induces chromosomal aberrations including an enhanced frequency of gene amplification (Smith et al., 1995), chromosome losses and gains, aberrant chromosome segregation and centrosome amplification (Saavedra et al., 1999). Inducible expression of activated H-Ras in PC-CL3 cells stimulated the formation of micronuclei containing chromosomes and chromosome fragments (Saavedra et al., 2000). Micronuclei with whole chromosomes arise as a consequence of spindle disruption; micronuclei containing chromosome fragments are typically generated by double strand DNA breaks. Although the effects of Ras on micronuclei formation were rapid, they were observed in only a small proportion of cells, perhaps due to the presence of wildtype p53 in these cells. This raises the interesting possibility that Ras predisposes thyroid cells to the acquisition of additional mutations by inducing genomic instability. Over time, cells harboring Ras mutations would acquire additional genetic and epigenetic changes that contribute to their full transformation. In this regard, it is interesting that Ras mutations occur at a higher frequency in follicular versus papillary carcinomas, given the higher degree of aneuploidy observed in follicular carcinomas (Fagin, 2002). It will be interesting to assess whether papillary tumors bearing B-Rafmutations exhibit similar chromosomal aberrations. Whether Ras induces genomic instability in primary human thyroid cells, which exhibit a more stable karyotype than do rodent cells, has not yet been determined.

While chromosomal instability could provide the mechanism for Ras-stimulated apoptosis, the low frequency of micronuclei formation versus the high frequency of apoptosis argues that these events are distinct (Shirokawa et al., 2000). Apoptosis was TSH-dependent, while micronuclei formation was insensitive to cAMP levels. Furthermore, the signaling pathways through which Ras stimulated micronuclei formation and apoptosis were distinct. Therefore, acute expression of activated Ras stimulates multiple signals leading to DNA damage and chromosomal instability in a small proportion of cells and apoptosis in most cells. The changes that occur in the small population of surviving cells that contribute to their survival in the presence of activated Ras remain to be identified.

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