Wasted by an elongation factor

Abstract

Some features of the wasted mouse phenotype are shared with the human autosomal recessive disorders ataxia–telangiectasia (AT) (caused by defects in the ATM gene) and Nijmegen breakage syndrome (NBS). These are immunodeficiency, ataxia, chromosomal instability and hypersensitivity of lymphocytes to ionizing radiation. However, an important difference is that fibroblasts from AT and NBS patients are hypersensitive to ionizing radiation, whereas fibroblasts derived from wasted mice exhibit normal sensitivity compared with those of wild-type mice[12xNordeen, S.K. et al. Mutat. Res. 1984; 140: 219–222Crossref | PubMed | Scopus (15)See all References][12]. This might suggest that there are more functional similarities between NBS and AT proteins than between NBS and EF1α2 proteins.Initially, the wasted mouse was suggested to be a mouse model for AT (Ref. [1xShultz, L.D., Sweet, H.O., Davisson, M.T., and Coman, D.R. Nature. 1982; 297: 402–404Crossref | PubMed | Scopus (69)See all References][1]), although AT and wasted were shown subsequently to map to non-homologous regions of the human and mouse genomes. Studies on ATM gene-targeted mice suggest that ATM is involved in the checkpoint machinery of the cell cycle, in signal transduction and in maintaining genome stability, particularly in response to DNA damage following ionizing radiation[13xLavin, M.F. and Shiloh, Y. Annu. Rev. Immunol. 1997; 15: 177–202Crossref | PubMed | Scopus (462)See all References][13]. It has been suggested that ATM could have a related function with the Saccharomyces cerevisiae signal-transduction protein Tor2p, based on its similar sequence. Inhibition of Tor2p causes an early block in translation and several other physiological changes characteristic of starved cells entering senescence[13xLavin, M.F. and Shiloh, Y. Annu. Rev. Immunol. 1997; 15: 177–202Crossref | PubMed | Scopus (462)See all References][13]. Therefore, the ATM and wst genes might be components of a signal-transduction pathway that regulates protein synthesis; the biological similarities between AT and wasted mice might partly arise from disruption of this pathway. Or, it might be possible that neurons and T cells use common apoptotic pathways and the concomitant neurodegeneration and immunodeficiency observed in AT and wst/wst is secondary to the defects in the ATM and wst genes. This common pathway could be triggered by cytokine imbalance seen in wasted mice and AT patients[14xLynn, W.S. and Wong, P.K. FASEB J. 1995; 9: 1147–1156PubMedSee all References, 15xLibertin, C.R., Ling-Indeck, L., Padilla, M., and Woloschak, G.E. Mol. Immunol. 1994; 31: 753–759Crossref | PubMed | Scopus (8)See all References].The important roles of translation elongation factors in cell cycle and cell growth have been well documented[16xRyazanov, A.G., Rudkin, B.B., and Spirin, A.S. FEBS Lett. 1991; 285: 170–175Crossref | PubMed | Scopus (67)See all References][16]. Of particular interest is the implication of these proteins in transformation and tumourigenesis[17xSonenberg, N. Curr. Opin. Cell Biol. 1993; 5: 955–960Crossref | PubMedSee all References][17]. For example, a putative oncogene, PTI1 (prostatic carcinoma tumour-inducing gene), shares strong sequence similarity to a truncated and mutated form of human Eef1a1 (Ref. [18xShen, R. et al. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6778–6782Crossref | PubMed | Scopus (103)See all References][18]). In addition, overexpression of Eef1g, the product of which, EF1γ< is a subunit of the EF1 complex, has been described in several malignancies, such as oesophageal carcinoma, adenocarcinomas and adenomas of the colon and stomach (Ref. [19xMimori, K. et al. Gut. 1996; 38: 66–70Crossref | PubMedSee all References][19]and references therein). Therefore, it would be worth investigating possible roles of other components of EF1 elongation factor complex such as EF1α, EF1β and EF1δ, in malignancies.It has been shown that in ageing Drosophila melanogaster there appears to be a reduction in the synthesis of EF1α and a subsequent decline in overall protein synthesis[20xWebster, G.C. and Webster, S.L. Mech. Ageing Dev. 1984; 24: 335–342Crossref | PubMed | Scopus (19)See all References][20]. Conversely, overexpression of EF1α seems to increase the fly life span[21xShepherd, J. et al. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7520–7521Crossref | PubMedSee all References][21]. Two genes have been described in Drosophila that encode isoforms of EF1α (Ref. [22xHovemann, B., Richter, S., Walldorf, U., and Cziepluch, C. Nucleic Acids Res. 1988; 16: 3175–3194Crossref | PubMed | Scopus (136)See all References][22]) and it would be interesting to see if the expression of either one in terminally differentiated cells protects these cells in some way and so delays or ameliorates the effects of ageing.The association of Eef1a2 with the wasted mutation is a reminder that we still have a surprising amount to learn about fundamental cellular mechanisms, such as translation, and the proteins involved in these processes. We look forward to the generation of the Eef1a2 gene-targeted mouse and further insights into the roles of translation elongation factors.