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Pharmacogenomics

Original Article

The Pharmacogenomics Journal advance online publication 20 July 2010; doi: 10.1038/tpj.2010.60

F Han1,4, H Yu1,4, C Tian1, H E Chen1, C Benedict-Alderfer1, Y Zheng1, Q Wang1,5, X Han1 and Q Y Zheng1,2,3

1. Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA
2. Department of Genetics, Case Western Reserve University, Cleveland, OH, USA
3. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

Correspondence: Dr QY Zheng, Department of Otolaryngology-HNS, Case Western Reserve University, 11100 Euclid Avenue, LKS 5045, Cleveland, OH 44106, USA. E-mail: qing.zheng@case.edu

4These authors contributed equally to this work.

5Current address: Department of Otolaryngology and HNS, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853 China.

Received 4 November 2009; Revised 4 June 2010; Accepted 14 June 2010; Published online 20 July 2010.
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Abstract

We report a novel mutation (erlong, erl) of the cadherin 23 (Cdh23) gene in a mouse model for DFNB12 characterized by progressive hearing loss beginning from postnatal day 27 (P27). Genetic and sequencing analysis revealed a 208?T >C transition causing an amino-acid substitution (70S–P). Caspase expression was upregulated in mutant inner ears. Hearing was preserved (up to 35-dB improvement) in pan-caspase inhibitor Z-VAD-FMK-treated mutants compared with untreated mutants (P<0.05). Outer hair cell (OHC) loss in the cochleae of Z-VAD-FMK-treated mutants was significantly reduced compared with those of untreated mice. Thus, the erl mutation can lead to hearing loss through apoptosis. This is the first genetic mouse model of hearing loss shown to respond to otoprotective drug therapy. The short interval from initial hearing loss to deafness (P27–P90) makes this model ideal for screening and validating otoprotective drugs.

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Daniel Herranz,

Maribel Muñoz-Martin,

Marta Cañamero,

Francisca Mulero,

Barbara Martinez-Pastor,

Oscar Fernandez-Capetillo

& Manuel Serrano

Abstract

Genetic overexpression of protein deacetylase Sir2 increases longevity in a variety of lower organisms, and this has prompted interest in the effects of its closest mammalian homologue, Sirt1, on ageing and cancer. We have generated transgenic mice moderately overexpressing Sirt1 under its own regulatory elements (Sirt1-tg). Old Sirt1-tg mice present lower levels of DNA damage, decreased expression of the ageing-associated gene p16Ink4a, a better general health and fewer spontaneous carcinomas and sarcomas. These effects, however, were not sufficiently potent to affect longevity. To further extend these observations, we developed a metabolic syndrome-associated liver cancer model in which wild-type mice develop multiple carcinomas. Sirt1-tg mice show a reduced susceptibility to liver cancer and exhibit improved hepatic protection from both DNA damage and metabolic damage. Together, these results provide direct proof of the anti-ageing activity of Sirt1 in mammals and of its tumour suppression activity in ageing- and metabolic syndrome-associated cancer.