Depletion of poly(A)-specific ribonuclease(PARN) arrests the cellcycle of human gastric cancer cells in a p53/p21-dependent pathway

【作者】 张丽娜； 闫永彬；

【机构】 清华大学；

【摘要】 Regulation of mRNA decay plays a crucial role in the post-transcription control of cellgrowth, survival, differentiation, death and senescence. Deadenylation is a rate-limitingstep in the silence and degradation the bulk of highly regulated mRNAs. However, thephysiological functions of various deadenylases have not been fully deciphered. In this research,we found that poly(A)-specific ribonuclease(PARN) was up-regulated in gastric tumortissues and gastric cancer cell lines MKN28 and AGS. The cellular function of PARNwas investigated by knocking down the endogenous PARN in the MKN28 and AGS cells.Our results showed that PARN-depletion significantly inhibited the proliferation of the twotypes of gastric cancer cells and promoted cell death, but did not significantly affect cellmotility and invasion. The depletion of PARN arrested the gastric cancer cells at the G0/G1 phase by up-regulating the expression levels of p53 and p21 but not p27. The mRNA stabilityof p53 was unaffected by PARN-depletion in both types of cells. A dramatic stabilizingeffect of PARN-depletion on p21 mRNA stability was observed in the AGS cells but notin the MKN28 cells. We further showed that the p21 3’-UTR triggered the action of PARN.The difference observed in the MKN28 and AGS cells and various stress conditions suggested that the action of PARN strongly relied on the protein expression profiles, which led to heterogeneity in the stability of PARN-targeted mRNAs.更多还原

【Abstract】 Regulation of mRNA decay plays a crucial role in the post-transcription control of cellgrowth, survival, differentiation, death and senescence. Deadenylation is a rate-limitingstep in the silence and degradation the bulk of highly regulated mRNAs. However, thephysiological functions of various deadenylases have not been fully deciphered. In this research,we found that poly(A)-specific ribonuclease(PARN) was up-regulated in gastric tumortissues and gastric cancer cell lines MKN28 and AGS. The cellular function of PARNwas investigated by knocking down the endogenous PARN in the MKN28 and AGS cells.Our results showed that PARN-depletion significantly inhibited the proliferation of the twotypes of gastric cancer cells and promoted cell death, but did not significantly affect cellmotility and invasion. The depletion of PARN arrested the gastric cancer cells at the G0/G1 phase by up-regulating the expression levels of p53 and p21 but not p27. The mRNA stabilityof p53 was unaffected by PARN-depletion in both types of cells. A dramatic stabilizingeffect of PARN-depletion on p21 mRNA stability was observed in the AGS cells but notin the MKN28 cells. We further showed that the p21 3’-UTR triggered the action of PARN.The difference observed in the MKN28 and AGS cells and various stress conditions suggested that the action of PARN strongly relied on the protein expression profiles, which led to heterogeneity in the stability of PARN-targeted mRNAs.更多还原