RNA Processing and Modification Protein, Carbon Catabolite Repression 4 (Ccr4), Arrests the Cell Cycle through p21-dependent and p53-independent Pathway

Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2012; 287(25):21045-57. DOI: 10.1074/jbc.M112.355321
Source: PubMed


Ccr4d is a new member of the Ccr4 (carbon catabolite repression 4) family of proteins that are implicated in the regulation
of mRNA stability and translation through mRNA deadenylation. However, Ccr4d is not believed to be involved in mRNA deadenylation.
Thus, its biological function and mechanistic activity remain to be determined. Here, we report that Ccr4d is broadly expressed
in various normal tissues, and the expression of Ccr4d is markedly down-regulated during cell cycle progression. We showed
that Ccr4d inhibits cell proliferation and induces cell cycle arrest at G1 phase. Our experiments further revealed that Ccr4d regulates the expression of p21 in a p53-independent manner. Mechanistic
studies indicated that Ccr4d strongly bound to the 3′-UTR of p21 mRNA, leading to the stabilization of p21 mRNA. Interestingly, we found that the expression of Ccr4d is down-regulated in various tumor tissues. Collectively, our
data indicate that Ccr4d functions as an anti-proliferating protein through the induction of cell cycle arrest via a p21-dependent
and p53-independent pathway and suggest that Ccr4d might have an important role in carcinogenesis.

21 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PARN, Nocturnin and Angel are three of the multiple deadenylases that have been described in eukaryotic cells. While each of these enzymes appear to target poly(A) tails for shortening and influence RNA gene expression levels and quality control, the enzymes differ in terms of enzymatic mechanisms, regulation and biological impact. The goal of this review is to provide an in depth biochemical and biological perspective of the PARN, Nocturnin and Angel deadenylases. Understanding the shared and unique roles of these enzymes in cell biology will provide important insights into numerous aspects of the post-transcriptional control of gene expression.
    Full-text · Article · Dec 2012 · Biochimica et Biophysica Acta
  • [Show abstract] [Hide abstract]
    ABSTRACT: Regulation of mRNA decay plays a crucial role in the post-transcription control of cell growth, survival, differentiation, death and senescence. Deadenylation is a rate-limiting step in the silence and degradation of the bulk of highly regulated mRNAs. However, the physiological functions of various deadenylases have not been fully deciphered. In this research, we found that poly(A)-specific ribonuclease (PARN) was upregulated in gastric tumor tissues and gastric cancer cell lines MKN28 and AGS. The cellular function of PARN was investigated by stably knocking down the endogenous PARN in the MKN28 and AGS cells. Our results showed that PARN-depletion significantly inhibited the proliferation of the two types of gastric cancer cells and promoted cell death, but did not significantly affect cell motility and invasion. The depletion of PARN arrested the gastric cancer cells at the G0/G1 phase by upregulating the expression levels of p53 and p21 but not p27. The mRNA stability of p53 was unaffected by PARN-knockdown in both types of cells. A significant stabilizing effect of PARN-depletion on p21 mRNA was observed in the AGS cells but not in the MKN28 cells. We further showed that the p21 3'-UTR triggered the action of PARN in the AGS cells. The dissimilar observations between the MKN28 and AGS cells as well as various stress conditions suggested that the action of PARN strongly relied on protein expression profiles of the cells, which led to heterogeneity in the stability of PARN-targeted mRNAs. Copyright © 2014. Published by Elsevier B.V.
    No preview · Article · Dec 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research