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J. Biol. Chem., Vol. 282, Issue 9, 6126-6135, March 2, 2007

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A Novel Regulator of Telomerase

S100A8 MEDIATES DIFFERENTIATION-DEPENDENT AND CALCIUM-INDUCED INHIBITION OF TELOMERASE ACTIVITY IN THE HUMAN EPIDERMAL KERATINOCYTE LINE HaCaT^*

Sabine Rosenberger¹, Irmgard S. Thorey, Sabine Werner^¶, and Petra Boukamp

From the Genetics of Skin Carcinogenesis, German Cancer Research Center Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, THP GmbH, Am Neuland 3, 82347 Bernried, Germany, and the ^¶Institute of Cell Biology, ETH Zuerich, Hoenggerberg, HPM D42, 8093 Zuerich, Switzerland

Recently we reported a differentiation-dependent inhibition of telomerase activity in human epidermis. Consistent with this observation we found that in keratinocyte cultures calcium-induced differentiation correlates with a decline in telomerase activity. To get further support for a role of calcium in the regulation of telomerase and to elucidate the underlying molecular mechanisms we investigated the effect of calcium on telomerase in the human epidermal keratinocyte line HaCaT. Treatment with thapsigargin, which increases intracellular calcium concentrations, inhibited telomerase activity without down-regulating the expression of hTERT (human telomerase reverse transcriptase). This observation together with the fact that increasing calcium reduced telomerase activity in cell-free extracts suggests that calcium directly interacts with the telomerase complex. This interaction could be mediated by the calcium-binding protein S100A8 as indicated by its ability to mimic the inhibitory effect of calcium. S100A8-induced reduction in telomerase activity was abrogated by S100A9. The ratio of both proteins remained constant in cells treated with thapsigargin, but their interactions were altered similarly in intact cells after thapsigargin treatment and in cell-free extracts in response to calcium. We hypothesize that calcium binds to S100A8/S100A9 complexes and alters their composition, thus enabling S100A8 to interact with the telomerase complex and inhibit its activity.

Received for publication, November 13, 2006 , and in revised form, December 27, 2006.

^* This work was supported by European Union Grants LSHG-CT-2003-503447 and LSHG-CT-2004-502943 (to P. B. and to P. B./S. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-6221-423446; Fax: 49-6221-423457; E-mail: s.rosenberger{at}dkfz.de.

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