MicroRNA-223 Regulates Cyclin E Activity by Modulating Expression of F-box and WD-40 Domain Protein 7

Xu, Yanfei; Sengupta, Tapan K.; Kukreja, Lokesh; Minella, Alex C.

doi:10.1074/jbc.m110.152306

Cited by 82 publications

(86 citation statements)

References 57 publications

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“…Although FBXW7 protein expression showed the tendency of positive correlation with mRNA expression levels and a similar pattern of prognostic outcomes (Figs S1,S2), its clinical significance remained limited. Regarding the regulation of FBXW7 expression, we speculate there may be epigenetic transcriptional regulation, (24) translational regulation by non-coding RNA (including micro RNA (25) ) because FBXW7 mutation is reported to be rarely observed (11,12) in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of ubiquitin ligase FBXW7 mRNA is associated with poor prognosis in breast cancer patients

Ibusuki¹,

Yamamoto²,

Shinriki

et al. 2010

Cancer Science

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FBXW7 is a cell cycle regulatory gene that ubiquitinates positive cell cycle regulators such as c-Myc and cyclin E, allowing for cell cycle exit. Defects in the FBXW7 gene that lead to cell cycle re-entry and expedite the G1-S transition is thought to be one of the causes of cancer development. However, its clinical importance for breast cancer patients remains undetermined. This prompted us to investigate its expression level in breast cancer patients to establish its clinical significance. The expression level of FBXW7 mRNA was assessed in 186 cases of primary invasive breast cancer. Correlations between FBXW7 mRNA expression and clinicopathological factors, prognoses and immunohistochemical expression levels of Ki-67, FBXW7, c-Myc and cyclin E were analyzed. In vitro investigation of FBXW7 gene silencing in a breast cancer cell line was conducted. FBXW7 mRNA was expressed at significantly lower levels in patients with high histological grade and hormone receptor-negative tumors. Patients with lower FBXW7 mRNA expression had a poorer prognosis for breast cancer-specific survival than those with higher expression. A high Ki-67 labeling index and positive cyclin E protein expression were significantly correlated with lower FBXW7 mRNA expression. In vitro, silencing FBXW7 enhanced expression of c-Myc and cyclin E proteins and upregulated both cell proliferation and G1-S transition. In breast cancer, reduced FBXW7 mRNA expression may have independent prognostic potential through the enhanced function of cell cycle regulatory proteins. (Cancer Sci 2011; 102: 439-445) R ecent studies have revealed that the ubiquitin-proteasome system plays many important roles in human carcinogenesis, such as in cell cycle progression, apoptosis, signal transmission and DNA repair. Frequent deregulation of E3 ligase components in breast cancer has led to their investigation as oncogenes or tumor suppressor genes. Major examples are the amplification and overexpression of Mdm2 and Skp2, mutation of BRCA1 in familial breast cancer and, more recently discovered, mutation and loss of expression of FBXW7 (F-box and WD repeat domain-containing 7).(1,2) FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligases and regulates positive cell cycle regulators such as c-Myc, cyclin E, c-JUN, Aurora A and Notch, molecules commonly implicated in many cancers (3) including breast cancer.(4,5) c-Myc is a transcription factor and has a crucial role in deciding whether or not mammalian cells divide. Cyclin E coordinates S-phase entry from either G1 or quiescence (G0), and constitutive expression of cyclin E leads to genomic instability. One notable function of FBXW7 is induction of cell cycle exit (to G0-phase) by c-Myc degradation, whereas cell cycle re-entry (G0 to G1) is regulated by p27 and its F-box regulator Skp2. Therefore, altered expression of FBXW7 is hypothesized to cause carcinogenesis and cancer development. (6,7) FBXW7 was first linked to carcinogenesis when mutations in FBXW7 were found in the brea...

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Section: Discussionmentioning

confidence: 99%

Reduced expression of ubiquitin ligase FBXW7 mRNA is associated with poor prognosis in breast cancer patients

Ibusuki¹,

Yamamoto²,

Shinriki

et al. 2010

Cancer Science

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“…miR-145 is decreased in a variety of malignancies including lung cancer and is now considered a tumor suppressor (26). miR-223 and miR-494 have been described as oncomirs targeting the tumor suppressors F-box and WD-40 domain protein 7 (27), and phosphatase and tensin homolog (28), respectively. A role in allergic airway disease has also been proposed for miR-145 (29).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cystic Fibrosis Transmembrane Conductance Regulator by MicroRNA-145, -223, and -494 Is Altered in ΔF508 Cystic Fibrosis Airway Epithelium

Oglesby

Chotirmall

McElvaney

et al. 2013

The Journal of Immunology

103

106

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Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) is altered in individuals with the ΔF508 CFTR mutation. We previously reported differential expression of microRNA (miRNA) in CF airway epithelium; however, the role of miRNA in regulation of CFTR expression here remains unexplored. In this study, we investigated the role of upregulated miRNAs in CFTR regulation in vivo in bronchial brushings from individuals homozygous or heterozygous for ΔF508 CFTR, validated our observations in vitro, and assessed the impact of defective chloride ion conductance, genotype, and colonization status on miRNA expression. miRNA target prediction was performed in silico, and expression of miRNA and target genes were measured by quantitative real-time PCR and/or Western blotting. Overexpression and inhibition studies were performed with pre-miRs or antimiRs, respectively, and a luciferase reporter gene was used to elucidate direct miRNA–target interactions. miR-145, miR-223, and miR-494 were upregulated in CF versus non-CF bronchial brushings and cell lines; in ΔF508 CFTR homozygotes versus heterozygotes; in subjects positive for P. aeruginosa; and in cells treated with a CFTR inhibitor or IL-1β. Reciprocal downregulation or upregulation of CFTR gene and/or protein expression was observed after miRNA manipulation and direct miRNA–target relationships demonstrated via a reporter system containing a wild type or mutated full-length CFTR 3′ untranslated region. Increased expression of miR-145, miR-223, and miR-494 in vivo in bronchial epithelium of individuals carrying the ΔF508 CFTR mutation correlates with decreased CFTR expression. Defective CFTR function, Pseudomonas colonization, and inflammation may affect miRNA expression and contribute to the regulation of ΔF508 CFTR.

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“…Interestingly, during the course of our work, the granulocyte-specific miR-223 was also identified as a regulator of FBW7 using a screen for miRNAs downregulated in cyclin E T74A, T393A knock-in erythroblasts. 29 However, according to our miRNA identification protocol (miRIP), only miR-27a fulfilled the criteria as a broadly expressed general regulator of FBW7 (see Materials and Methods, Fig. 1E and Sup.…”

Section: Discussionmentioning

confidence: 99%

MiRNA-27a controls FBW7/hCDC4-dependent cyclin E degradation and cell cycle progression

Lerner¹,

Lundgren²,

Akhoondi³

et al. 2011

Cell Cycle

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MicroRNA-223 Regulates Cyclin E Activity by Modulating Expression of F-box and WD-40 Domain Protein 7

Cited by 82 publications

References 57 publications

Reduced expression of ubiquitin ligase FBXW7 mRNA is associated with poor prognosis in breast cancer patients

Reduced expression of ubiquitin ligase FBXW7 mRNA is associated with poor prognosis in breast cancer patients

Regulation of Cystic Fibrosis Transmembrane Conductance Regulator by MicroRNA-145, -223, and -494 Is Altered in ΔF508 Cystic Fibrosis Airway Epithelium

MiRNA-27a controls FBW7/hCDC4-dependent cyclin E degradation and cell cycle progression

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