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Small molecule–based reversible reprogramming of cellular lifespan

A Retraction to this article was published on 01 July 2008

A Corrigendum to this article was published on 01 February 2007

This article has been updated

Abstract

Most somatic cells encounter an inevitable destiny, senescence1,2. Little progress has been made in identifying small molecules that extend the finite lifespan of normal human cells. Here we show that the intrinsic 'senescence clock' can be reset in a reversible manner by selective modulation of the ataxia telangiectasia–mutated (ATM) protein and ATM- and Rad3-related (ATR) protein with a small molecule, CGK733. This compound was identified by a high-throughput phenotypic screen with automated imaging. Employing a magnetic nanoprobe technology, magnetism-based interaction capture (MAGIC)3, we identified ATM as the molecular target of CGK733 from a genome-wide screen. CGK733 inhibits ATM and ATR kinase activities and blocks their checkpoint signaling pathways with great selectivity. Consistently, siRNA-mediated knockdown of ATM and ATR induced the proliferation of senescent cells, although with lesser efficiency than CGK733. These results might reflect the specific targeting of the kinase activities of ATM and ATR by CGK733 without affecting any other domains required for cell proliferation.

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Figure 1: Identification of a small molecule that reverses senescence.
Figure 2: Molecular target identification based on MAGIC technology.
Figure 3: Effects of CGK733 on ATM and ATR and related kinase signaling pathways.
Figure 4: Effects of CGK733 on kinase signaling pathways related to ATM and ATR.

Change history

  • 22 December 2006

    In the version of this article initially published, no competing financial interests were declared. The authors now declare that they have competing interests that might be perceived to influence the results and discussion reported in this paper, which are detailed in a declaration of competing financial interests accompanying the article. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank T. de Lange, R.Y. Tsien, J. Campisi, J. Chung, G.P. Nolan, M.R. Stampfer and D.S. Lim for gifts of reagents. This work was supported by CGK Co. Ltd. and was also partially supported by the Korea Research Foundation grant (KRF-2005-C00097), the Korea Health 21 R&D Project (A040042) and the Chemical Genomics program from the Korean Ministry of Science and Technology.

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Correspondence to Tae Kook Kim.

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Competing interests

T.K.K. receives support for research programs from CGK Co., Ltd. M.K. has a part-time consulting relationship with CGK Co., Ltd.*

*Note: In the version of this article initially published, no competing financial interests were declared. The authors now declare that they have competing interests that might be perceived to influence the results and discussion reported in this paper, which are detailed in a declaration of competing financial interests accompanying the article. The error has been corrected in the HTML and PDF versions of the article.

Supplementary information

Supplementary Fig. 1

Establishment of cellular senescence by overexpression of TRF2ΔBΔM. (PDF 35 kb)

Supplementary Fig. 2

Reversal of replicative senescence of BJ and HMEC cells by CGK733. (PDF 160 kb)

Supplementary Fig. 3

Karyotypes of the senescent cells induced to proliferate by CGK733. (PDF 7 kb)

Supplementary Fig. 4

Effects of CGK733 on ATM and ATR kinase activities inside cells. (PDF 63 kb)

Supplementary Fig. 5

Effects of ATM/ATR siRNAs and CGK733 on the proliferation of senescent cells. (PDF 8 kb)

Supplementary Fig. 6

Synthesis of KU-55933 and a CGK733-biotin derivative. (PDF 26 kb)

Supplementary Fig. 7

Effects of KU-55933 on replicative senescence. (PDF 7 kb)

Supplementary Methods (PDF 128 kb)

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Won, J., Kim, M., Kim, N. et al. Small molecule–based reversible reprogramming of cellular lifespan. Nat Chem Biol 2, 369–374 (2006). https://doi.org/10.1038/nchembio800

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  • DOI: https://doi.org/10.1038/nchembio800

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