Expression of RNA splice variants
The critical issue is the importance and specific role of hTERT splicing variants in regulation of telomerase activity and as a potential marker of health status and survival. Despite the provocative predictions for activities of products of splice variants, little direct evidence has accumulated.
Of particular interest however, the splice variant deleted for alternative sequence a is a dominant-negative inhibitor of hTERT activity in cell lines (Colgin et al. 2000; Saraste et al. 1990; Yi et al. 2000). The variant hTERT that causes these effects lacks a mere 12 amino acids, although these 12 aa contain conserved RT motif A. When over expressed in immortalized fibroblasts and carcinoma cells, the variant inhibited telomerase activity. Furthermore, these cells also exhibited progressively shortening telomeres and eventually apoptotic cell death or a senescence-like state. Importantly, these data suggest that telomerase activity is controlled in part by post-transcriptional events.
Most of the data regarding telomerase splice variants is descriptive, mainly observations of the quality and quantity of splicing variants of hTERT in normal, immortal, and cancer cells. Although some correlations are observed (e.g., in kidney, different splice variants appear dependent on the level of telomerase activity (Ulaner et al. 1998) a number of different variants are expressed in cancer cells (Barclay et al. 2005; Fujiwara-Akita et al. 2005; Fujiwara et al. 2004; Hisatomi et al. 2003; Nagao et al. 2004; Ulaner et al. 2000; Yokoyama et al. 2001) without apparent commonality. The complexity of the system and low expression and activity levels in some cells add to the difficultness of deciphering the intricacies of telomerase regulation.