Wnt Preserves Telomeres

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Sci. Signal.  26 Jun 2012:
Vol. 5, Issue 230, pp. ec173
DOI: 10.1126/scisignal.2003335

Telomeres are repetitive sequences that protect the ends of chromosomes, but they shrink as cells divide and age. Telomerase, which is composed of both an enzymatic subunit (TERT) and an RNA component, promotes genomic stability by lengthening telomeres that have become shortened and is particularly important for stem cell renewal and tumor cell survival. The amount of telomerase present in a cell is key to telomere maintenance, and many transcription factors both positively and negatively regulate the transcription of Tert (see the Perspective by Greider). Hoffmeyer et al. reported that the transcription factor β-catenin, which is protected from degradation by activation of the Wnt signaling pathway, directly promoted expression of Tert in stem cells and in cancer cells. Compared with wild-type mouse embryonic stem (ES) cells, Tert transcripts, TERT protein, and telomerase activity were increased in ES cells producing a form of β-catenin that is not readily degraded and were reduced in ES cells lacking β-catenin. Chromatin immunoprecipitation assays indicated that β-catenin was present at the Tert promoter in wild-type ES cells and in ES cells producing the stabilized form of β-catenin. Treating wild-type ES cells with Wnt3a increased Tert expression and the amount of β-catenin detected at the Tert promoter. The presence of β-catenin at the Tert promoter correlated with transcriptional activation and was required for recruitment of a histone methyltransferase to the promoter. The transcription factor Klf4, which is an important stem cell maintenance factor, was also present at the Tert promoter, where it formed a complex with β-catenin. Klf4 was required for accumulation of β-catenin at the Tert promoter but was unable to stimulate Tert expression in the absence of β-catenin. β-catenin also bound to the Tert promoter in intestinal and neural stem cells from adult mice, in mouse intestinal cancer cells, and in two human carcinoma cell lines. These results indicate that β-catenin promotes genomic stability by cooperating with Klf4 to stimulate the production of telomerase, consistent with β-catenin’s role in stem cell maintenance and cancer progression.

K. Hoffmeyer, A. Raggioli, S. Rudloff, R. Anton, A. Hierholzer, I. Del Valle, K. Hein, R. Vogt, R. Kemler, Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science 336, 1549–1554 (2012). [Abstract] [Full Text]

C. W. Greider, Wnt regulates TERT—Putting the horse before the cart. Science 336, 1519–1520 (2012). [Abstract] [Full Text]

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