The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a

Becker, Therese M.; Haferkamp, Sebastian; Dijkstra, Menno K; Scurr, Lyndee L.; Frausto, Monika; Diefenbach, Eve; Scolyer, Richard A.; Reisman, David; Mann, Graham J.; Kefford, Richard; Rizos, Helen

doi:10.1186/1476-4598-8-4

Cited by 55 publications

(46 citation statements)

References 34 publications

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“…In contrast to the small intestinal epithelium, where Brg1 loss was incompatible with long-term crypt retention, Brg1 deficient crypts were preserved in the large intestinal epithelium for an extensive period. Of interest, despite the generally accepted role of Brg1 as a tumor suppressor [41][42][43][44], we observed no signs of neoplastic transformation in Brg1 negative crypts even at late time points, indicating tissue-specific differences in Brg1 function as a tumor suppressor.…”

Section: Brg1 Loss Is Compensated By Brm Upregulation In Large Intestmentioning

confidence: 43%

Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner

et al. 2013

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Brg1 is a chromatin remodeling factor involved in mediation of a plethora of signaling pathways leading to its participation in various physiological processes both during development and in adult tissues. Among other signaling pathways, the Wnt pathway has been proposed to require Brg1 for transactivation of its target genes. Given the pivotal role of the Wnt pathway in the maintenance of normal intestinal homeostasis, we aimed to investigate the effects of Brg1 loss on the intestinal physiology. To this end, we deleted Brg1 in the murine small and large intestinal epithelia using a range of transgenic approaches. Pan-epithelial loss of Brg1 in the small intestine resulted in crypt ablation, while partial Brg1 deficiency led to gradual repopulation of the intestinal mucosa with wild-type cells. In contrast, Brg1 loss in the large intestinal epithelium was compensated by upregulation of Brm. We propose that while Brg1 is dispensable for the survival and function of the progenitor and differentiated cells in the murine intestinal epithelium, it is essential for the maintenance of the stem cell population in a tissuespecific manner.

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Section: Brg1 Loss Is Compensated By Brm Upregulation In Large Intestmentioning

confidence: 43%

Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner

et al. 2013

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“…Indeed, our results demonstrate that KRP5 binds to various loci on chromatin, possibly via an interaction with the chromatin-remodeling factor AtBAF60, to modulate gene expression. Such a mechanism has been reported in mammalian cells, where the cell cycle inhibitor p16 interacts with the SWI/ SNF complex Brg1 (Becker et al, 2009). Among KRP5 targets, we identified CDC20 in our ChIP-seq experiment.…”

Section: Discussionmentioning

confidence: 69%

Multiple Functions of Kip-Related Protein5 Connect Endoreduplication and Cell Elongation

et al. 2013

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Despite considerable progress in our knowledge regarding the cell cycle inhibitor of the Kip-related protein (KRP) family in plants, less is known about the coordination of endoreduplication and cell differentiation. In animals, the role of cyclindependent kinase (CDK) inhibitors as multifunctional factors coordinating cell cycle regulation and cell differentiation is well documented and involves not only the inhibition of CDK/cyclin complexes but also other mechanisms, among them the regulation of transcription. Interestingly, several plant KRPs have a punctuated distribution in the nucleus, suggesting that they are associated with heterochromatin. Here, one of these chromatin-bound KRPs, KRP5, has been studied in Arabidopsis (Arabidopsis thaliana). KRP5 is expressed in endoreduplicating cells, and loss of KRP5 function decreases endoreduplication, indicating that KRP5 is a positive regulator of endoreduplication. This regulation relies on several mechanisms: in addition to its role in cyclin/CDK kinase inhibition previously described, chromatin immunoprecipitation sequencing data combined with transcript quantification provide evidence that KRP5 regulates the transcription of genes involved in cell wall organization. Furthermore, KRP5 overexpression increases chromocenter decondensation and endoreduplication in the Arabidopsis trithoraxrelated protein5 (atxr5) atxr6 double mutant, which is deficient for the deposition of heterochromatin marks. Hence, KRP5 could bind chromatin to coordinately control endoreduplication and chromatin structure and allow the expression of genes required for cell elongation.

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“…Deletion or mutation of the BRG1 gene was found in lung, breast, prostate, and melanoma cancer cell lines (28,30,31,33,40). The SNF5 gene was also found inactivated in MRTs and downregulated in epithelioid sarcomas (25, 41).…”

Section: Discussionmentioning

confidence: 99%

Loss of SNF5 Expression Correlates with Poor Patient Survival in Melanoma

Lin

Wong

Martinka

et al. 2009

Clinical Cancer Research

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Purpose: Aberrant expression of SWI/SNF chromatin remodeling complex is involved in cancer development. The tumor suppressor SNF5, the core subunit of SWI/SNF complex, has been shown to regulate cell differentiation, cell cycle control, and apoptosis. To investigate the role of SNF5 in the development of melanoma, we examined the expression of SNF5 in melanocytic lesions at different stages and analyzed the correlation between SNF5 expression and clinicopathologic variables and patient survival. Experimental Design: Using tissue microarry and immunohistochemistry, we evaluated SNF5 staining in 51 dysplastic nevi, 88 primary melanomas, and 48 metastatic melanomas. We studied chemosensitivity of melanoma cells with reduced SNF5 expression by siRNA using cell survival and apoptosis assays. Results: SNF5 expression was reduced in metastatic melanoma compared with dysplastic nevi (P = 0.005), in advanced primary melanoma (Clark's level V) compared with low risk Clark's level II melanoma (P = 0.019), and in melanoma at sun-exposed sites compared with sun-protected sites (P = 0.044). Furthermore, we showed a strong correlation between negative SNF5 expression and a worse 5-year survival in melanoma patients (P = 0.016). Multivariate Cox regression analysis revealed that negative SNF5 expression is an independent prognostic factor to predict patient outcome in primary melanomas (P = 0.031). Finally, we showed that knockdown of SNF5 in melanoma cell lines resulted in significant chemoresistance. Conclusions: Our data indicate that SNF5 may be an important marker for human melanoma progression and prognosis as well as a potential therapeutic target. (Clin Cancer Res 2009;15(20):6404-11) Human cutaneous malignant melanoma is a life-threatening skin cancer, for its ability to metastasize rapidly and its resistance to conventional radiotherapy and chemotherapy (1, 2). Although melanoma accounts for only 4% of skin cancers, it is responsible for 80% of deaths from skin cancer (3). Furthermore, although melanoma is curable through early diagnosis and surgical excision (4), up to 20% of patients will develop metastatic tumor due to its highly invasive and metastatic properties (5). Consequently, metastatic melanoma patients have a poor prognosis, with median survival of only 6 to 10 months and <5% of the patients surviving >5 years (4, 6, 7). SWI/SNF ATP-dependent chromatin-remodeling complex is a 2-Mda multsubunit complex first identified in yeast and highly conserved among eukaryotes (8). SWI/SNF complexes play essential roles in transcriptional regulation, contribute to the control of cellular processes, such as proliferation and differentiation, and also are involved in DNA repair by altering the accessibility of UV-damaged DNA-binding proteins to DNA lesions (9-13). SNF5, also known as INI1/BAF47/SMARCB1, is the core subunit of mammalian SWI/SNF complex. Many genetic evidences have defined SNF5 as a tumor suppressor gene in humans and mice. In mice, homozygous deletion of SNF5 is embryonic lethal, and heterozy...

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The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a

Cited by 55 publications

References 34 publications

Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner

Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner

Multiple Functions of Kip-Related Protein5 Connect Endoreduplication and Cell Elongation

Loss of SNF5 Expression Correlates with Poor Patient Survival in Melanoma

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