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Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation.

ABSTRACT: Coordinated regulation of cell proliferation is vital for epithelial tissue homeostasis, and uncontrolled proliferation is a hallmark of carcinogenesis. A growing body of evidence indicates that epithelial tight junctions (TJs) play a role in these processes, although the mechanisms involved are poorly understood. In this study, we identify and characterize a novel plasma membrane pool of cyclin D1 with cell-cycle regulatory functions. We have determined that the zonula occludens (ZO) family of TJ plaque proteins sequesters cyclin D1 at TJs during mitosis, through an evolutionarily conserved class II PSD-95, Dlg, and ZO-1 (PDZ)-binding motif within cyclin D1. Disruption of the cyclin D1/ZO complex through mutagenesis or siRNA-mediated suppression of ZO-3 resulted in increased cyclin D1 proteolysis and G(0)/G(1) cell-cycle retention. This study highlights an important new role for ZO family TJ proteins in regulating epithelial cell proliferation through stabilization of cyclin D1 during mitosis.

SUBMITTER: Capaldo CT

PROVIDER: S-EPMC3093320 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation.

Capaldo Christopher T CT Koch Stefan S Kwon Michael M Laur Oskar O Parkos Charles A CA Nusrat Asma A

Molecular biology of the cell 20110316 10

Coordinated regulation of cell proliferation is vital for epithelial tissue homeostasis, and uncontrolled proliferation is a hallmark of carcinogenesis. A growing body of evidence indicates that epithelial tight junctions (TJs) play a role in these processes, although the mechanisms involved are poorly understood. In this study, we identify and characterize a novel plasma membrane pool of cyclin D1 with cell-cycle regulatory functions. We have determined that the zonula occludens (ZO) family of ...[more]

PMID: 21411630

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Project description:The sterol regulatory-element binding protein (SREBP) family of transcription factors regulates cholesterol, fatty acid, and triglyceride synthesis and metabolism. However, they are also targeted by the ubiquitin ligase Fbw7, a major tumor suppressor, suggesting that they could regulate cell growth. Indeed, enhanced lipid synthesis is a hallmark of many human tumors. Thus, the SREBP pathway has recently emerged as a potential target for cancer therapy. We have previously demonstrated that one of these transcription factors, SREBP1, is stabilized and remains associated with target promoters during mitosis, suggesting that the expression of these target genes could be important as cells enter G1 and transcription is restored. Activation of cyclin D-cdk4/6 complexes is critical for the phosphorylation and inactivation of the retinoblastoma protein (Rb) family of transcriptional repressors and progression through the G1 phase of the cell cycle. Importantly, the cyclin D-cdk4/6-Rb regulatory axis is frequently dysregulated in human cancer. In the current manuscript, we demonstrate that SREBP1 activates the expression of cyclin D1, a coactivator of cdk4 and cdk6, by binding to an E-box in the cyclin D1 promoter. Consequently, inactivation of SREBP1 in human liver and breast cancer cell lines reduces the expression of cyclin D1 and attenuates Rb phosphorylation. Rb phosphorylation in these cells can be rescued by restoring cyclin D1 expression. On the other hand, expression of active SREBP1 induced the expression of cyclin D1 and increased the phosphorylation of Rb in a manner dependent on cyclin D1 and cdk4/6 activity. Inactivation of SREBP1 resulted in reduced expression of cyclin D1, attenuated phosphorylation of Rb, and reduced proliferation. Inactivation of SREBP1 also reduced the insulin-dependent regulation of the cyclin D1 gene. At the same time, SREBP1 is known to play an important role in supporting lipid synthesis in cancer cells. Thus, we propose that the SREBP1-dependent regulation of cyclin D1 coordinates cell proliferation with the enhanced lipid synthesis required to support cell growth.

Project description:Accumulating evidence has indicated that aberrant expression of long non-coding RNAs (lncRNAs) is an important oncogenic factor. The aim of the present study was to investigate the role of LINC01296, an lncRNA that exerts a tumor?promoting function in many cancers, in the regulation of proliferation, metastasis and the cell cycle of osteosarcoma. The expression of LINC01296 in osteosarcoma tissues and adjacent healthy tissues of 30 patients was analyzed by quantitative real?time PCR (qRT?PCR). The relationship between LINC01296 expression and the survival of patients with osteosarcoma was also explored. The expression levels of LINC01296 in osteosarcoma cells and normal cells were compared. LINC01296 knockdown and overexpression were performed in MG63 and HOS8603 osteosarcoma cells by transfecting LINC01296 shRNA and an expression plasmid respectively, followed by investigation of the changes on cell proliferation, migration, apoptosis and cell cycle arrest. Western blotting was used to analyze the changes of cell cycle regulators. Cyclin D1 knockdown and overexpression were carried out to verify the interaction between LINC01296 and cyclin D1. LINC01296 overexpression was demonstrated as a biomarker of osteosarcoma, which was closely correlated with the poor survival of patients with osteosarcoma. A high expression of LINC01296 was observed in osteosarcoma cells, which was closely associated with enhanced proliferation, invasion, and migration of osteosarcoma cells. Cyclin D1 expression was positively correlated with the expression of LINC01296 in osteosarcoma cells. Cyclin D1 knockdown or overexpression played a deterministic role in mediating the effect of LINC01296 on osteosarcoma cells. LINC01296 is an oncogenic lncRNA in osteosarcoma. The proliferation, invasion and migration of osteosarcoma cells could be effectively retarded by inhibition of LINC01296. The cancer?promoting effect of LINC01296 on osteosarcoma was determined by cyclin D1.

Dataset Information

Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation.

Publications

Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation.

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