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  current news   Press   selected story    
     
  13th July 2010  
  PCBP1 Suppresses the Translation of Metastasis-Associated PRL-3 Phosphatase
 
 




Authors
Haihe Wang1, Leah Vardy2, Cheng Peow Tan1, Jia Min Loo3, Ke Guo1, Jie Li1, Seng Gee Lim1,4, Jianbiao Zhou5, Wee Joo Chng6, Siok Bian Ng7, Hui Xiang Li8 and Qi Zeng1*

1 - Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore 138648.
  
2 - Institute of Medical Biology, A*STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, Immunos, Singapore 138648.
    
3 - The Rockefeller University, 1230 York Ave., Box 342, New York, NY 10065.
  
4 - Departments of Gastroenterology & Hepatology, National University Hospital, Singapore 119074.
  
5 - Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456.
   
6 - Department of Haematology-Oncology, National University Cancer Institute, Singapore National University Health System, 5 Lower Kent Ridge Road, S119074.
   
7 - Department of Pathology, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.
   
8 - The First Affiliated Hospital of Zheng Zhou University, 40 Da Xue Lu, Henan, Zheng Zhou 450052, China. 
  
*Corresponding author: Dr. Qi Zeng, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673.

Published in Cancer Cell 18, 5262, July 13, 2010.

Abstract
Overexpression of PRL-3 phosphatase is associated with the progression of diverse human cancers. We show that the overexpression of PRL-3 protein is not directly associated with its transcript levels, indicating the existence of an underlying posttranscriptional regulation. The 5’ UTR of PRL-3 mRNA possesses triple GCCCAG motifs capable of suppressing mRNA translation through interaction with PCBP1 (PolyC-RNAbinding protein 1), which retards PRL-3 mRNA transcript incorporation into polyribosomes. Overexpression of PCBP1 inhibits PRL-3 expression and inactivates AKT; while knockdown of PCBP1 causes upregulation of PRL-3 protein levels, activation of AKT, and promotion of tumorigenesis. An inverse correlation between protein levels of PRL-3 and PCBP1 in human primary cancers supports the clinical relevance.

Significance
Metastasis is the most malevolent aspect of cancer. Upregulation of PRL-3 causes metastases, but the mechanism regulating PRL-3 overexpression is poorly understood. Our identification of PCBP1 as an upstream regulator of PRL-3 translation reveals a molecular mechanism responsible for the overexpression of PRL-3 in cancer. The inverse correlation between PCBP1 and PRL-3 protein levels in several human cancers suggests that PCBP1-mediated PRL-3 regulation is of physiological and clinical relevance. The axis of PCBP1→PRL-3→AKT may be a pathway in controlling cancer progression. The finding of PCBP1 as a tumor suppressor is highly significant as a similar mechanism may be regulating other cancer genes.

Highlights:
• PRL-3 protein is upregulated in diverse human cancers
• PCBP1 suppresses PRL-3 translation via the 5’UTR of the PRL-3 mRNA
• PCBP1 and PRL-3 protein levels were inversely correlated in human cancers.

The axis of PCBP1→PRL-3→AKT is a novel pathway in cancer cell signaling

Figure Legends:
A. Immunohistochemistry analyses on a human colon cancer. The section showed that PRL-3 protein was expressed in cancerous but not in normal epithelia. A red arrowhead indicates the transition area between cancerous and normal colon tissue. Scale Bar, 100 µm.

B. A working model for the action of PCBP1 in regulating the translation of the PRL-3 mRNA. When PCBP1 protein levels are high, PCBP1 binds to the 6-base GC-motifs located at the 5’UTR of the PRL-3 mRNA, resulting in repression of PRL-3 translation (upper panel); while when PCBP1 protein levels are low, PCBP1 does not bind to the GC-motifs, and it releases the inhibition of PRL-3 translation. The PRL-3 translation then proceeds with high efficiency (lower panel).

For more information on Dr. Qi ZENG’s lab, please click here.