MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein
Nucleic acids research, 2012•academic.oup.com
The functional association between intronic miRNAs and their host genes is still largely
unknown. We found that three gene loci, which produced miR-26a and miR-26b, were
embedded within introns of genes coding for the proteins of carboxy-terminal domain RNA
polymerase II polypeptide A small phosphatase (CTDSP) family, including CTDSPL,
CTDSP2 and CTDSP1. We conducted serum starvation-stimulation assays in primary
fibroblasts and two-thirds partial-hepatectomies in mice, which revealed that miR-26a/b and …
unknown. We found that three gene loci, which produced miR-26a and miR-26b, were
embedded within introns of genes coding for the proteins of carboxy-terminal domain RNA
polymerase II polypeptide A small phosphatase (CTDSP) family, including CTDSPL,
CTDSP2 and CTDSP1. We conducted serum starvation-stimulation assays in primary
fibroblasts and two-thirds partial-hepatectomies in mice, which revealed that miR-26a/b and …
Abstract
The functional association between intronic miRNAs and their host genes is still largely unknown. We found that three gene loci, which produced miR-26a and miR-26b, were embedded within introns of genes coding for the proteins of carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase (CTDSP) family, including CTDSPL, CTDSP2 and CTDSP1. We conducted serum starvation-stimulation assays in primary fibroblasts and two-thirds partial-hepatectomies in mice, which revealed that miR-26a/b and CTDSP1/2/L were expressed concomitantly during the cell cycle process. Specifically, they were increased in quiescent cells and decreased during cell proliferation. Furthermore, both miR-26 and CTDSP family members were frequently downregulated in hepatocellular carcinoma (HCC) tissues. Gain- and loss-of-function studies showed that miR-26a/b and CTDSP1/2/L synergistically decreased the phosphorylated form of pRb (ppRb), and blocked G1/S-phase progression. Further investigation disclosed that miR-26a/b directly suppressed the expression of CDK6 and cyclin E1, which resulted in reduced phosphorylation of pRb. Moreover, c-Myc, which is often upregulated in cancer cells, diminished the expression of both miR-26 and CTDSP family members, enhanced the ppRb level and promoted the G1/S-phase transition. Our findings highlight the functional association of miR-26a/b and their host genes and provide new insight into the regulatory network of the G1/S-phase transition.
Oxford University Press