Cell Cycle Arrest and Repression of Cyclin D1 Transcription by INI1/hSNF5

Zhang, Zhi Kai; Davies, Kelvin P.; Allen, Jeffrey C.; Zhu, Liang; Pestell, Richard G.; Zagzag, David; Kalpana, Ganjam V.

doi:10.1128/mcb.22.16.5975-5988.2002

Cited by 211 publications

(205 citation statements)

References 49 publications

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“…This result indicates that VAESBJ represents a unique model to investigate the role of SMARCB1 inactivation in the context of epithelioid sarcoma. Because in MRTs cells, SMARCB1 tumor suppressor activity has been shown to impinge on cell proliferation (29,30), apoptosis (31), senescence (20,27), and cell motility (21), we investigated these phenotypes in SMARCB1-deleted VAESBJ epithelioid sarcoma cell line. Here, we provide evidence that SMARCB1 restoration in this cell line affects cell proliferation, enhances the sensitivity to genotoxic stress, and reduces cell migration.…”

Section: Discussionmentioning

confidence: 99%

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

Brenca

Rossi

Lorenzetto

et al. 2013

Molecular Cancer Therapeutics

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Epithelioid sarcoma is a rare soft tissue neoplasm that usually arises in the distal extremities of young adults. Epithelioid sarcoma presents a high rate of recurrences and metastases and frequently poses diagnostic dilemmas. We previously reported loss of tumor suppressor SMARCB1 protein expression and SMARCB1 gene deletion in the majority of epithelioid sarcoma cases. Unfortunately, no appropriate preclinical models of such genetic alteration in epithelioid sarcoma are available. In the present report, we identified lack of SMARCB1 protein due to a homozygous deletion of exon 1 and upstream regulatory region in epithelioid sarcoma cell line VAESBJ. Restoration of SMARCB1 expression significantly affected VAESBJ cell proliferation, anchorage-independent growth, and cell migration properties, thus supporting the causative role of SMARCB1 loss in epithelioid sarcoma pathogenesis. We investigated the translational relevance of this genetic background in epithelioid sarcoma and showed that SMARCB1 ectopic expression significantly augmented VAESBJ sensitivity to gamma irradiation and acted synergistically with flavopiridol treatment. In VAESBJ, both activated ERBB1/EGFR and HGFR/MET impinged on AKT and ERK phosphorylation. We showed a synergistic effect of combined inhibition of these 2 receptor tyrosine kinases using selective small-molecule inhibitors on cell proliferation. These observations provide definitive support to the role of SMARCB1 inactivation in the pathogenesis of epithelioid sarcoma and disclose novel clues to therapeutic approaches tailored to SMARCB1-negative epithelioid sarcoma.

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Section: Discussionmentioning

confidence: 99%

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

Brenca

Rossi

Lorenzetto

et al. 2013

Molecular Cancer Therapeutics

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“…Indeed, several groups have documented that hSNF5/INI1 re-expression in MRT cell lines leads to the accumulation of cells in the G 0 /G 1 phase of the cell-cycle (Betz et al, 2002;Versteege et al, 2002;Zhang et al, 2002). This hSNF5/INI1-induced cell-cycle arrest requires a functional RB/E2F pathway and is reversible (Medjkane et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

et al. 2007

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ATP-dependent SWI/SNF chromatin remodeling complexes regulate cell-cycle and play critical roles in a variety of differentiation pathways. The core subunit SNF5/INI1 is a tumor suppressor that is inactivated in a highly aggressive childhood cancer of unknown cellular origin, termed malignant rhabdoid tumor (MRT). The highly undifferentiated phenotype of this tumor suggests that the loss-of-function of hSNF5/INI1 impairs specific differentiation programs of the MRT parental cell. Based on the hypothesis that these programs might be reinitialized upon hSNF5/INI1 re-expression in MRTs, we show that some MRT cell lines can differentiate toward the adipogenic lineage. We further show that the knock down of the SNF5/INI1 subunit abrogates adipocyte differentiation of murine 3T3-L1 preadipocytes and of human mesenchymal stem cells. Finally, we provide evidence that hSNF5/INI1 cooperates with C/EBPb and PPARc2 transcriptional regulators to activate the expression of adipocyte-specific genes. These data indicate that not only the ATPase subunit of the SWI/SNF complex, but also SNF5/INI1 is required for adipocyte differentiation. They further show that MRT cell lines harbor an adipogenic differentiation potential and that the tumor suppressor role of the SNF5/INI1 subunit may rely on its ability to regulate the balance between cell proliferation and differentiation.

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“…The presence of the above-mentioned E box in the promoter of cyclin D1 was reported previously; yet, the importance of it as a functional element for cyclin D1 regulation had not been explored (Herber et al, 1994;Zhang et al, 2002). Transcription factors binding to E box elements include c-Myc, USF, and Snail (Blackwell et al, 1990;Nieto, 2002;Adhikary and Eilers, 2005;Galibert, 2005, 2006;De Craene et al, 2005).…”

Section: C-myc Recognizes the E Box/e2f Region In Cyclin D1 Promotermentioning

confidence: 99%

Cyclin D1 Is Transcriptionally Down-Regulated by ZO-2 via an E Box and the Transcription Factor c-Myc

Huerta¹,

Muñoz²,

Tapia

et al. 2007

MBoC

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Recent reports have indicated the participation of tight junction (TJ) proteins in the regulation of gene expression and cell proliferation. Here, we have studied the role of zona occludens (ZO)-2, a TJ peripheral protein, in the regulation of cyclin D1 transcription. We found that ZO-2 down-regulates cyclin D1 transcription in a dose-dependent manner. To understand how ZO-2 represses cyclin D1 promoter activity, we used deletion analyses and found that ZO-2 negatively regulates cyclin D1 transcription via an E box and that it diminishes cell proliferation. Because ZO-2 does not associate directly with DNA, electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) assay were used to identify the transcription factors mediating the ZO-2-repressive effect. c-Myc was found to bind the E box present in the cyclin D1 promoter, and the overexpression of c-Myc augmented the inhibition generated by ZO-2 transfection. The presence of ZO-2 and c-Myc in the same complex was further demonstrated by immunoprecipitation. ChIP and reporter gene assays using histone deacetylases (HDACs) inhibitors demonstrated that HDACs are necessary for ZO-2 repression and that HDAC1 is recruited to the E box. We conclude that ZO-2 down-regulates cyclin D1 transcription by interacting with the c-Myc/E box element and by recruiting HDAC1.

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Cell Cycle Arrest and Repression of Cyclin D1 Transcription by INI1/hSNF5

Cited by 211 publications

References 49 publications

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

Cyclin D1 Is Transcriptionally Down-Regulated by ZO-2 via an E Box and the Transcription Factor c-Myc

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