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Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors

Oncogene volume 20, pages 1497–1508 (2001)Cite this article

Abstract

Telomeres are essential for cell survival and have been implicated in the mitotic control. The telomeric protein Pin2/TRF1 controls telomere elongation and its expression is tightly regulated during cell cycle. We previously reported that overexpression of Pin2/TRF1 affects mitotic progression. However, the role of Pin2/TRF1 at the interface between cell division and cell survival remains to be determined. Here we show that overexpression of Pin2 induced apoptosis in cells containing short telomeres, but not in cells with long telomeres. Furthermore, before entering apoptosis, Pin2-expressing cells first accumulated in mitosis and strongly stained with the mitosis-specific MPM2 antibody. Moreover, Pin2-induced apoptosis is potentiated by arresting cells in mitosis, but suppressed by accumulating cells in G1. In addition, overexpression of Pin2 also resulted in activation of caspase-3, and its proapoptotic activity was significantly reduced by inhibition of caspase-3. These results indicate that up-regulation of Pin2/TRF1 can specifically induce entry into mitosis and apoptosis, likely via a mechanism related to activation of caspase-3. Significantly, we also found that, out of 51 human breast cancer tissues and 10 normal controls examined, protein levels of Pin2/TRF1 in tumors were significantly lower than in normal tissues, as detected by immunoblotting analysis and immunocytochemistry. Since down-regulation of Pin2/TRF1 allows cells to maintain long telomeres, these results suggest that down-regulation of Pin2/TRF1 may be important for cancer cells to extend their proliferative potential.

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Acknowledgements

We thank B Neel, L Cantley, J Yuan and Y Shiloh for constructive discussion, G Wulf for providing the human breast cancer tissues, T de Lange for long telomere HeLa cells, T Niu for helping statistical analysis and Y Shiloh for the A-T cell line. G Wulf and M Nakamura are a DOD Breast Cancer Program and a Human Frontier Research Program fellows, respectively. KP Lu is a Pew Scholar and a Lymphoma and Leukemia Society Scholar. The work was supported by grants from Nathan Shock Center on Aging and NIH (R01GM56230) to KP Lu.

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  1. Division of Hematology/Oncology, Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02215, Massachusetts, MA, USA

    Shuji Kishi, Gerburg Wulf, Masafumi Nakamura & Kun Ping Lu

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  1. Shuji Kishi
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Kishi, S., Wulf, G., Nakamura, M. et al. Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors. Oncogene 20, 1497–1508 (2001). https://doi.org/10.1038/sj.onc.1204229

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