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Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer

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Published on: April 13, 2015

Alternatively spliced telomerase reverse transcriptase variants lacking telomerase activity stimulate cell

Radmila Hrdlicková¹, Jirí Nehyba, Henry R Bose

¹Section of Molecular Genetics and Microbiology, School of Biological Science, and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, USA.

Molecular and Cellular Biology

|August 22, 2012

Summary

Novel alternatively spliced variants of telomerase reverse transcriptase (TERT) lacking catalytic activity were found to stimulate cell proliferation. These TERT variants influence cell growth independently of telomerase function, impacting Wnt signaling pathways.

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Area of Science:

Molecular Biology
Cell Biology
Cancer Research

Background:

Telomerase reverse transcriptase (TERT) is crucial for telomere maintenance.
Alternatively spliced (AS) TERT variants are increasingly recognized in various cellular contexts.
The functional significance of AS TERT variants lacking catalytic activity remains largely unexplored.

Purpose of the Study:

To identify and characterize novel alternatively spliced variants of TERT.
To investigate the functional impact of AS TERT variants, particularly those lacking telomerase activity, on cell proliferation.
To explore the signaling pathways influenced by these novel TERT variants.

Main Methods:

Identification of novel AS TERT variants in human and chicken cells using molecular cloning techniques.
Expression analysis of AS TERT variants in different cell types and tissues.
Functional assays including cell proliferation rate measurements and Wnt signaling pathway analysis.
Gene silencing using small interfering RNA (siRNA) to assess the role of endogenous AS TERT variants.

Main Results:

Discovery of eight human and six chicken novel AS TERT variants.
A human variant, Δ4-13, lacking the catalytic domain, was expressed in various cell types.
Overexpression of Δ4-13 TERT variant increased cell proliferation without affecting telomerase activity.
Knockdown of endogenous Δ4-13 TERT variant reduced cell proliferation.
Δ4-13 TERT variant expression stimulated Wnt signaling.
Chicken AS TERT variants with reduced telomerase activity also enhanced cell proliferation.

Conclusions:

Naturally occurring AS TERT variants that lack telomerase activity can stimulate cell proliferation.
These findings reveal a novel, telomerase-independent mechanism by which TERT variants influence cell growth.
AS TERT variants may play a significant role in cellular processes beyond telomere maintenance, including Wnt signaling.