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.