1. ¹Institute of Clinical Pathology, University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria
2. ²Institute of Cancer Research, University of Vienna, Borschkegasse 8a, Vienna A-1090, Austria
3. ³Department of Vascular Biology and Thrombosis Research, Vienna International Research Co-operation Center (VIRCC), University of Vienna, Brunnerstrae 59, Vienna A-1235, Austria

Correspondence: G Krupitza, Institute of Clinical Pathology, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43-1-40 400/3487; Fax: +43-1-405 34 02; E-mail: g.krupitza@akh-wien.ac.at

Received 22 January 2003; Revised 1 July 2003; Accepted 25 July 2003; Published online 5 September 2003.

Abstract

Cell division cycle 25A (Cdc25A) was shown to colocalise both with nuclear and cytoplasmic proteins. Recently, we have demonstrated that overexpressed Cdc25A promoted the survival of rat 423 cells through indirect activation of PKB-protein kinase B. Using a Cdc25A:ER fusion protein, which can be shuttled from the cytoplasm into the nucleus, the present investigation evidences that the antiapoptotic effect of Cdc25A was restricted to its cytoplasmic localisation in rat 423 cells. In contrast, nuclear Cdc25A overexpression caused dephosphorylation and nuclear retention of the proapoptotic transcription factor Forkhead in rhabdomyosarcoma-like 1 (FKHRL1) in human N.1 ovarian carcinoma cells. This resulted in the increased constitutive expression of the FKHRL1 targets Fas ligand and Bim, and promoted apoptosis. Thus, the Cdc25A oncogene, which was found to be frequently overexpressed in certain human cancers, can increase or decrease the susceptibility to apoptosis depending on the cell-type-specific subcellular distribution.