Cancer surveys最新文献

Mutations that constitutively activate the alpha chains of Gs and Gi2 by inhibiting their intrinsic GTPase activity are present in human endocrine tumours. The gsp oncogene is mainly found in pituitary GH secreting tumours and thyroid hyperfunctioning adenomas, where it induces a constitutive activation of the adenylyl cyclase-cAMP pathway. In pituitary and thyroid cells, this signal leads to abnormal proliferation and a persistent activation of differentiated functions. The gip2 oncogene has been identified in tumours of the ovary and adrenal cortex. Although the mechanisms of the oncogenic action of mutationally activated alpha i2 are less clear than those of alpha s, the protein can induce transformation of certain cell types. At least five other alpha chains, which share with alpha s and alpha i2 common structural and functional mechanisms of GTP hydrolysis, activate mitogenic pathways leading to transformation. In addition, the G protein beta gamma subunits clearly control signals involved in cell growth. So far, there is no evidence for mutations of these molecules in human tumours. Further studies will tell us whether at present we know of only two members of a much larger family of G protein oncogenes.

The probability of a mouse cell becoming fully transformed in vivo or in vitro is enormously greater than that of a human cell. The number of events in tumour progression is similar in rodent and human cells, and it is unlikely that the difference in neoplastic transformation frequency can be explained on the basis of gene mutation in oncogenes and tumour suppressor genes. Instead, it is proposed that mouse cells may be (a) more subject to destabilization of the karyotype, (b) have less efficient check point cell cycle controls after DNA is damaged and/or (c) have less stringent epigenetic controls of gene activity, based on DNA methylation. Much evidence exists that mouse or rat cells are less efficient in DNA repair, maintenance of DNA methylation and other aspects of DNA metabolism. These relate to the difference in longevity in these and other mammalian species. Ageing is likely to be due to the failure of cell and tissue maintenance. Long lived species invest more in various somatic maintenance mechanisms than do short lived ones, and this includes protection against neoplastic transformation. The future study of the basis of the difference between human and mouse or rat cells in resistance to transformation is likely to yield important insights into the sequential events in tumour progression.

In E coli, new spontaneous mutations can arise in bacteria that are non-dividing and in which there is little or no DNA synthesis. These mutations are almost invariably those that enable the cell to resume growth, a phenomenon that has been termed directed or adaptive mutation. Evidence is accumulating from studies with DNA repair deficient strains that damage produced by endogenous mutagens may be an important source of such mutations. A DNA lesion that can miscode can explain the apparent adaptive behaviour since if a "mutant" RNA transcript confers sufficient advantage that the cell is triggered into a cycling state, the ensuing round of DNA replication will be likely to fix the mutation by means of a DNA miscoding event. The most important lesion in this respect appears to be 8-oxoG, which can pair equally well with adenine or cytosine and so give rise to G to T transversions. It is responsible for almost half the G to T transversions arising in non-growing repair proficient bacteria. Alkylations contribute to the production of both transitions and transversions but only those at A:T base pairs are important in repair proficient bacteria. There is also a report of a lesion susceptible to UvrA,B,C dependent excision repair, but whether it is important in bacteria possessing excision repair has not been addressed. Data on mammalian cells are almost non-existent, but there is evidence that point mutations can occur in vivo in postmitotic neurons. The underlying assumption that there is little or no DNA synthesis in non-dividing bacteria has been challenged by recent data suggesting that there may be extensive cryptic DNA turnover.

Recent insights into the action of TP53 have uncovered signal transduction pathways that maintain genomic integrity. TP53 was the first gene demonstrated to be involved in these pathways, but mutation of several other genes can have a similar terminal effect. The characterization of these signal transduction pathways should provide further targets for the improvement of neoplastic diagnosis as well as therapeutic efficacy.

Heterotrimeric G proteins are key players in a transmembrane signalling system that is used by every cell to regulate its basal functions as well as to integrate its specific functions into the whole organism. The complexity of this task is reflected by the diversity of molecular components involved therein and the variety of their potential interactions that have been described thus far. G protein mediated cellular signalling obviously represents a network of interacting pathways that are highly dynamic and are subject to short and long term regulatory processes that adapt the system to changing conditions. The identification of signalling molecules and the description of their functions have provided the foundation for understanding signal transduction processes involving G proteins. Much work, however, is still required to provide an understanding of how these molecular events are orchestrated in time and in space in a living cell.