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

Oncogene volume 22, pages 5325–5337 (2003)Cite this article

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.

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Abbreviations

SL2:

Schneider's Drosophila cell line 2

kb:

kilobase(s)

PCR:

polymerase chain reaction

5′-UTR:

5′-untranslated region

IRES:

internal ribosome entry site

PAGE:

polyacrylamide gel electrophoresis

mRNA:

messenger RNA

RRL:

rabbit reticulocyte lysate

HRV:

human rhinovirus

LUC:

luciferase

VEGF:

vascular endothelial growth factor

PDGF:

platelet-derived growth factor

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Acknowledgements

We are indebted to Dr AE Willis for pRF and pGL3RHRV plasmids, Drs Guntram Suske and Etty Benveniste for pPacO and pPacSp1 plasmids, and Dr Philip Marsden for pPac-UEts-1 plasmid. This work was supported in part by National Institutes of Health Grants CA64539 and GM59475, and by Department of Defense Grant DAMD17-02-1-0073. J-TZ is a recipient of a Career Investigator Award from the American Lung Association.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, I.U. Cancer Center and Walther Oncology Center/Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, 46202, IN, USA

    Baoguang Han, Zizheng Dong, Yang Liu, Qun Chen & Jian-Ting Zhang

  2. National Institute of Infectious Diseases, Tokyo, Japan

    Katsuyuki Hashimoto

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Correspondence to Jian-Ting Zhang.

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Han, B., Dong, Z., Liu, Y. et al. Regulation of constitutive expression of mouse PTEN by the 5′-untranslated region. Oncogene 22, 5325–5337 (2003). https://doi.org/10.1038/sj.onc.1206783

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