RAS Is Regulated by the let-7 microRNA Family

Cell. 2005 Mar 11;120(5):635-47. doi: 10.1016/j.cell.2005.01.014.

Abstract

MicroRNAs (miRNAs) are regulatory RNAs found in multicellular eukaryotes, including humans, where they are implicated in cancer. The let-7 miRNA times seam cell terminal differentiation in C. elegans. Here we show that the let-7 family negatively regulates let-60/RAS. Loss of let-60/RAS suppresses let-7, and the let-60/RAS 3'UTR contains multiple let-7 complementary sites (LCSs), restricting reporter gene expression in a let-7-dependent manner. mir-84, a let-7 family member, is largely absent in vulval precursor cell P6.p at the time that let-60/RAS specifies the 1 degrees vulval fate in that cell, and mir-84 overexpression suppresses the multivulva phenotype of activating let-60/RAS mutations. The 3'UTRs of the human RAS genes contain multiple LCSs, allowing let-7 to regulate RAS expression. let-7 expression is lower in lung tumors than in normal lung tissue, while RAS protein is significantly higher in lung tumors, providing a possible mechanism for let-7 in cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics*
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Cell Transformation, Neoplastic / genetics
  • Down-Regulation / genetics*
  • Gene Expression Regulation, Developmental / genetics*
  • Genes, Reporter / genetics
  • HeLa Cells
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • MicroRNAs / genetics*
  • Molecular Sequence Data
  • ras Proteins / genetics*

Substances

  • 3' Untranslated Regions
  • Caenorhabditis elegans Proteins
  • MicroRNAs
  • let-7 microRNA, C elegans
  • let-60 protein, C elegans
  • ras Proteins

Associated data

  • GENBANK/AY941100
  • GENBANK/AY941101