MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein.
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.
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510275, PR China.
Ying
Y
Zhu
Yang
Y
Lu
Qi
Q
Zhang
Jing-Jing
JJ
Liu
Tuan-Jie
TJ
Li
Jian-Rong
JR
Yang
Chunxian
C
Zeng
Shi-Mei
SM
Zhuang
D000818:Animals; D045744:Cell Line, Tumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*
D035683:MicroRNAs; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D016160:Retinoblastoma Protein; C528163:MIRN26 microRNA, human; C413483:CTDSP1 protein, human