Regulation of constitutive expression of mouse PTEN by the 5′-untranslated region

Baoguang Han, Zizheng Dong, Yang Liu, Qun Chen, Katsuyuki Hashimoto, Jian Ting Zhang

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

PTEN tumor suppressor serves as a major negative regulator of survival signaling mediated by PI3 kinase/AKT/protein kinase B pathway, and is inactivated in various human tumors. Elucidation of mechanisms responsible for PTEN expression is important for providing insight into strategies to control the loss of PTEN expression in human cancers. Although recent studies suggested that p53 and Egr-1 can modulate induced PTEN expression, the mechanism responsible for ubiquitous constitutive expression of PTEN remains elusive. PTEN mRNA contains a highly conserved and GC-rich 5′-untranslated region (5′-UTR). Recently, it has been shown that the long 5′-UTR sequences of several growth-regulated mRNAs contain promoters that can generate mRNAs with shorter 5′-UTRs. In this paper, we tested whether the 5′-UTR sequence of mouse PTEN contains a promoter that is responsible for constitutive expression of PTEN. We found that the long 5′-UTR sequence of mouse PTEN severely inhibits translation of PTEN and a heterologous gene firefly luciferase. Deletion of the most 5′-UTR sequence would enhance translation efficiency 100-fold. We also showed that the 5′-UTR sequence of mouse PTEN does not have an internal ribosome entry site (IRES) that can mediate cap-independent initiation of translation. Instead, we found that the 5′-UTR sequence of mouse PTEN contains a strong promoter that drives the production of a transcript with shorter 5′-UTRs, which can be translated with higher efficiency. This promoter was mapped to the region between -551 and -220 bases upstream of the translation start codon. Cotransfection analysis using Drosophila SL2 cells showed that Sp1 is one of the major transcription factors that can constitutively activate this promoter. Two endogenous PTEN transcripts with 5′-UTRs of 193 and 109 bases were found in DU145 and H226 cell lines. Based on these observations, we conclude that the PTEN expression may be regulated at both transcriptional and translational levels, and that the 5′-UTR sequence of PTEN contains a promoter that is responsible for constitutive PTEN expression.

Original languageEnglish (US)
Pages (from-to)5325-5337
Number of pages13
JournalOncogene
Volume22
Issue number34
DOIs
StatePublished - Aug 14 2003

Keywords

  • 5′-UTR
  • IRES
  • Promoter
  • PTEN

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Han, B., Dong, Z., Liu, Y., Chen, Q., Hashimoto, K., & Zhang, J. T. (2003). Regulation of constitutive expression of mouse PTEN by the 5′-untranslated region. Oncogene, 22(34), 5325-5337. https://doi.org/10.1038/sj.onc.1206783