This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Brenkman, A. B. Articles by Burgering, B. M.T. Search for Related Content PubMed PubMed Citation Articles by Brenkman, A. B. Articles by Burgering, B. M.T.

The Peptidyl-Isomerase Pin1 Regulates p27^kip1 Expression through Inhibition of Forkhead Box O Tumor Suppressors

¹ Department of Metabolic and Endocrine Diseases and Netherlands Metabolomics Centre, ² Department of Physiological Chemistry and Centre for Biomedical Genetics, and ³ Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands

Requests for reprints: Boudewijn M.T. Burgering, Department of Physiological Chemistry and Centre for Biomedical Genetics, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Phone: 31-88756-8918; Fax: 31-30253-9035; E-mail: b.m.t.burgering{at}umcutrecht.nl.

Key Words: FOXO • p27^kip1 • Pin1

The Forkhead box O (FOXO) protein family is an evolutionarily conserved subclass of transcription factors recently identified as bona fide tumor suppressors. Preventing the accumulation of cellular damage due to oxidative stress is thought to underlie its tumor-suppressive role. Oxidative stress, in turn, also feedback controls FOXO4 function. Regulation of this process, however, is poorly understood but may be relevant to the ability of FOXO to control tumor suppression. Here, we characterize novel FOXO4 phosphorylation sites after increased cellular oxidative stress and identify the isomerase Pin1, a protein frequently found to be overexpressed in cancer, as a critical regulator of p27^kip1 through FOXO4 inhibition. We show that Pin1 requires these phosphorylation events to act negatively on FOXO4 transcriptional activity. Consistent with this, oxidative stress induces binding of Pin1 to FOXO, thereby attenuating its monoubiquitination, a yet uncharacterized mode of substrate modulation by Pin1. We have previously shown that monoubiquitination is involved in controlling nuclear translocation in response to cellular stress, and indeed, Pin1 prevents nuclear FOXO4 accumulation. Interestingly, Pin1 acts on FOXO through stimulation of the activity of the deubiquitinating enzyme HAUSP/USP7. Ultimately, this results in decreased transcriptional activity towards target genes, including the cell cycle arrest gene p27^kip1. Notably, in a primary human breast cancer panel, low p27^kip1 levels inversely correlated with Pin1 expression. Thus, Pin1 is identified as a novel negative FOXO regulator, interconnecting FOXO phosphorylation and monoubiquitination in response to cellular stress to regulate p27^kip1. [Cancer Res 2008;68(18):7597–605]