Journal Article

Cell cycle-dependent translation of p27 involves a responsive element in its 5′-UTR that overlaps with a uORF

Ulrich Göpfert, Michael Kullmann and Ludger Hengst

in Human Molecular Genetics

Volume 12, issue 14, pages 1767-1779
Published in print July 2003 | ISSN: 0964-6906
Published online July 2003 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddg177
Cell cycle-dependent translation of p27 involves a responsive element in its 5′-UTR that overlaps with a uORF

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p27Kip1 regulates cell proliferation by binding to and modulating the activity of cyclin-dependent kinases. The CDK inhibitor is haploinsufficient for tumor suppression and reduced p27 activity is fundamental for the development of many human malignancies. Consistently, reduced p27 protein provides independent prognostic information in various tumors including breast, prostate, colon and gastric carcinomas. In normal cells, p27 protein increases in growth arrest but also oscillates during cell cycle progression. Expression of p27 is regulated through mechanisms including transcription, translation and ubiquitin-mediated degradation. Each of these pathways may contribute to deregulation of p27 in hyperproliferative diseases. p27 translation increases in proliferating cells during G1 phase and declines as cells enter S phase. To investigate the mechanisms of p27 translational control, we analyzed fragments of the p27 transcript for their contribution to cell cycle regulated translation. We found that an element in the p27 5′-UTR can render reporter translation cell cycle sensitive with maximal translation in G1-arrested cells. This novel element of 114 nt contains a G/C-rich hairpin domain that is predicted to form multiple stable stemloops and also overlaps with a small upstream ORF (uORF). Both structures contribute to cell cycle-regulated translation. The uORF can be translated in vitro and its sequence and position are highly conserved in mice and chickens. Interestingly, the precise sequence or the length of the uORF-encoded peptide are not important for p27 translation, consistent with the idea that ribosomal recruitment to its initiation codon rather than the translation product itself contributes to the regulation.

Journal Article.  9748 words.  Illustrated.

Subjects: Genetics and Genomics

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