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Molecular and Cellular Biology, January 2008, p. 539-550, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00584-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Prosurvival Effect of DHCR24/Seladin-1 in Acute and Chronic Responses to Oxidative Stress{triangledown}

Katrin Kuehnle,1,2* Arames Crameri,1,{dagger} Roland E. Kälin,2,§ Paola Luciani,3 Susanna Benvenuti,3 Alessandro Peri,3 Francesca Ratti,4 Monica Rodolfo,4 Luka Kulic,1 Frank L. Heppner,2,§ Roger M. Nitsch,1 and M. Hasan Mohajeri1,{ddagger}

Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland,1 Department of Pathology, Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland,2 Endocrine Unit, Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders, University of Florence, 50134 Florence, Italy,3 Unit of Melanoma Genetics, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy4

Received 3 April 2007/ Returned for modification 19 June 2007/ Accepted 22 October 2007

DHCR24/seladin-1, a crucial enzyme in sterol synthesis, is of lower abundance in brain areas affected by Alzheimer's disease. While high levels of DHCR24/seladin-1 exert antiapoptotic function by conferring resistance against oxidative stress, the molecular mechanism for this protective effect is not fully understood. Here we show that DHCR24/seladin-1 expression is up-regulated in an acute response and down-regulated in a chronic response to oxidative stress. High levels of DHCR24/seladin-1 were associated with elevated cholesterol concentrations and a general increase in cholesterol biosynthesis upon oxidative stress exposure in neuroblastoma SH-SY5Y cells. DHCR24/seladin-1 overexpression conferred resistance to oxidative stress in a cholesterol-dependent manner. Mutating the reductase activity within DHCR24/seladin-1 abolished this protective effect. Conversely, DHCR24/seladin-1 levels diminished upon chronic exposure to oxidative stress. Low levels of DHCR24/seladin-1 were associated with reduced p53 levels, independent of DHCR24 activity and cholesterol concentrations. Additionally, ablation of DHCR24/seladin-1 prevented apoptosis of primary neurons in a p53-dependent manner and reduced the response of critical p53 targets due to deficient stabilization of p53 and therefore elevated p53 ubiquitination and degradation. Our findings reveal a dual capacity of DHCR24/seladin-1, which appears to be involved in two mechanistically independent prosurvival effects, exerting an acute response and a chronic response to oxidative stress.

* Corresponding author. Mailing address: Swiss Academy of Medical Sciences, Petersplatz 13, 4051 Basel, Switzerland. Phone: 41612699031. Fax: 41612699039. E-mail: k.kuehnle{at}samw.ch

{triangledown} Published ahead of print on 5 November 2007.

{dagger} Present address: Quintiles Transnational Corp., 4053 Basel, Switzerland.

§ Present address: Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

{ddagger} Present address: DSM Nutritional Products, 4002 Basel, Switzerland.

Molecular and Cellular Biology, January 2008, p. 539-550, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00584-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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