ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein
Department of Pharmacology, University of Montreal, Québec, Canada. Oncogene
(Impact Factor: 8.46).
04/2011; 30(36):3846-61. DOI: 10.1038/onc.2011.100
The ADP-ribosylation factors (ARFs) 1 and 6 are small GTP-binding proteins, highly expressed and activated in several breast cancer cell lines and are associated with enhanced migration and invasiveness. In this study, we report that ARF1 has a critical role in cell proliferation. Depletion of this GTPase or expression of a dominant negative form, which both resulted in diminished ARF1 activity, led to sustained cell-growth arrest. This cellular response was associated with the induction of senescent markers in highly invasive breast cancer cells as well as in control mammary epithelial cells by a mechanism regulating retinoblastoma protein (pRB) function. When examining the role of ARF1, we found that this GTPase was highly activated in normal proliferative conditions, and that a limited amount could be found in the nucleus, associated with the chromatin of MDA-MB-231 cells. However, when cells were arrested in the G(0)/G(1) phase or transfected with a dominant negative form of ARF1, the total level of activated ARF1 was markedly reduced and the GTPase significantly enriched in the chromatin. Using biochemical approaches, we demonstrated that the GDP-bound form of ARF1 directly interacted with pRB, but not other members of this family of proteins. In addition, depletion of ARF1 or expression of ARF1T(31)N resulted in the constitutive association of pRB and E2F1, thereby stabilizing the interaction of E2F1 as well as pRB at endogenous sites of target gene promoters, preventing expression of E2F target genes, such as cyclin D1, Mcm6 and E2F1, important for cell-cycle progression. These novel findings provide direct physiological and molecular evidence for the role of ARF1 in controlling cell proliferation, dependent on its ability to regulate pRB/E2F1 activity and gene expression for enhanced proliferation and breast cancer progression.
Figures in this publication
Available from: Peirong Lu
- "ARF is activated by various growth factors, such as hepatocyte growth factor , colony stimulating factor-1 , and epidermal growth factor (EGF) . Recent studies have demonstrated that the ARF family is a key regulator of tumor cell proliferation, migration, and invasion [7,8]. Endothelial cell migration and proliferation are important steps in the formation of CNV. "
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ABSTRACT: To evaluate the roles of ADP-ribosylation factor (ARF) in alkali-induced corneal neovascularization (CNV).
CNV was induced by alkali injury and compared in ARF1 inhibitor- or vehicle-treated mice 3 weeks after injury. Angiogenic and apoptosis factor expression in corneas after injury was quantified with reverse-transcription PCR. Human retinal endothelial cell apoptosis induced by ARF1 inhibitor was detected with flow cytometry.
The mRNA expression of ARF1 was augmented in the corneas after alkali injury. Compared with vehicle-treated mice, ARF1 inhibitor-treated mice exhibited impaired CNV 3 weeks after injury, as evidenced by corneal whole mount CD31-staining. Concomitantly, the enhancement of intraocular vascular endothelial growth factor expression was reduced in ARF1 inhibitor-treated mice compared to control mice after injury. Moreover, local administration of the ARF1 inhibitor after alkali injury enhanced intraocular caspase-3 expression. ARF1 inhibitor treatment can significantly induce human retinal endothelial cell apoptosis.
The ARF1 inhibitor can induce the regression of alkali-induced CNV through increased endothelial cell apoptosis and downregulated intracorneal VEGF expression. ARF1 is an effective intervention target for CNV.
Molecular vision 12/2012; 18:2947-53. · 1.99 Impact Factor
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ABSTRACT: RNA-seq has the potential to discover genes created by complex chromosomal rearrangements. 'Fusion' genes formed by the breakage and re-joining of two different chromosomes have repeatedly been implicated in the development of cancer. However, although RNA-seq can detect these fusion events, normal cells are also characterized by read-through fusions across adjacent genes in the genome, or by transcription-induced chimeras (TICs). In this paper, we detected TICs events in normal tissue samples. The information derived from our analysis indicates the presence of a significant number of TICs in normal tissues. Some of these TICs can be associated with cancer development. In some cases TIC expression is corroborated by a large number of reads and their expression is significantly spread over different tissues. Our data highlight that TICs could be erroneously associated with cancer aberrations if RNA-seq analysis is only evaluated in tumor samples without considering the parallel analysis of normal tissue samples associated with the tumor.
Complex, Intelligent and Software Intensive Systems (CISIS), 2012 Sixth International Conference on; 01/2012
Available from: Chang Yi-Fen
Cancer Science 02/2012; · 3.52 Impact Factor
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