Alternatively Spliced Telomerase Reverse Transcriptase Variants Lacking Telomerase Activity Stimulate Cell Proliferation

Abstract

Eight human and six chicken novel alternatively spliced (AS) variants oftelomerase reverse transcriptase (TERT) were identified, including ahuman variant (Delta 4-13) containing an in-frame deletion which removedexons 4 through 13, encoding the catalytic domain of telomerase. Thisvariant was expressed in telomerase-negative normal cells and tissues aswell as in transformed telomerase-positive cell lines and cells whichemploy an alternative method to maintain telomere length. Theoverexpression of the Delta 4-13 variant significantly elevated theproliferation rates of several cell types without enhancing telomeraseactivity, while decreasing the endogenous expression of this variant byuse of small interfering RNA (siRNA) technology reduced cellproliferation. The expression of the Delta 4-13 variant stimulated Wntsignaling. In chicken cells, AS TERT variants containing internaldeletions or insertions that eliminated or reduced telomerase activityalso enhanced cell proliferation. This is the first report thatnaturally occurring AS TERT variants which lack telomerase activitystimulate cell proliferation.