p16  Is Required for hSNF5 Chromatin Remodeler-induced Cellular Senescence in Malignant Rhabdoid Tumor Cells

Oruetxebarria, Igor; Venturini, Francesca; Kekarainen, Tuija; Houweling, Ada; Zuijderduijn, Lobke M.P.; Mohd‐Sarip, Adone; Vries, Robert G.J.; Hoeben, Rob C.; Verrijzer, C. Peter

doi:10.1074/jbc.m309333200

Cited by 154 publications

(158 citation statements)

References 56 publications

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“…Notably, different from what was reported for MRT cell models, restoration of SMARCB1 in VAESBJ expression failed to result in premature senescence. In MRTs cells, such a response relied on p16 activation (20). The fact that VAESBJ cells carry homozygous deletion of CDKN2A/p16 locus may account for the attenuation of the senescent phenotype in this cell line.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…For comparison, selected experiments were conducted in parallel in G401 malignant rhabdoid tumor cell line ( Supplementary Fig. S3), which was previously reported to be affected by SMARCB1 restoration (7,8,20).…”

Section: Smarcb1 Loss Sustains Vaesbj Tumorigenic Propertiesmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

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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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“…For the generation of a lentiviral expression vector for Mdm4, HA-Mdm4 (de Graaf et al, 2003) was cloned into pLV-CMVbc-GFP (Oruetxebarria et al, 2004) Table 1 for sequences). Subsequently, fragments containing the H1-promoter and cloned nucleotides were recloned into the PstI site of the lentiviral pRRL-CMV-GFP vector (Carlotti et al, 2004).…”

Section: Plasmids and Lentiviral Infectionsmentioning

confidence: 99%

Role of Mdm4 in drug sensitivity of breast cancer cells

et al. 2010

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The p53 tumor suppressor protein is frequently mutated in human tumors. It is thought that the p53 pathway is indirectly impaired in the remaining tumors, for example by overexpression of its important regulators Mdm2 and Mdm4, making them attractive targets for the development of anti-cancer agents. Recent studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anti-cancer therapy. To investigate this possibility, we studied the drug sensitivity of several breast cancer cell lines containing wild-type p53, but expressing different Mdm4 levels. We show that endogenous Mdm4 levels can affect the sensitivity of breast cancer cells to anti-cancer agents, but in a cell line-dependent manner and depending on an intact apoptotic response. Furthermore, treatment with the non-genotoxic agent Nutlin-3 sensitizes cells for doxorubicin, showing that activation of p53 by targeting its regulators is an efficient strategy to decrease cell viability of breast cancer cells. These results confirm a function of Mdm4 in determining the efficacy of chemotherapeutic agents to induce apoptosis of cancer cells in a p53-dependent manner, although additional undetermined factors also influence the drug response. Targeting Mdm4 to sensitize tumor cells for chemotherapeutic drugs might be a strategy to effectively treat tumors harboring wild-type p53.

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“…Chromatin immunoprecipitation experiments have demonstrated the presence of hSWI/SNF on the cyclin D promoter, where it repressed transcription . Chromatin immunoprecipitation also demonstrated that hSWI/SNF members occupy the p16 INK4a and p21 WAF1/CIP1 promoters in vivo, where their presence is correlated with increased transcription (Lee et al, 2002;Kadam and Emerson, 2003;Kang et al, 2004;Oruetxebarria et al, 2004;Chai et al, 2005). The hSWI/SNF complex also regulates a diverse group of other mammalian target genes.…”

Section: Discussionmentioning

confidence: 97%

Members of the hSWI/SNF chromatin remodeling complex associate with and are phosphorylated by protein kinase B/Akt

et al. 2006

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In an adenosine triphosphate (ATP)-dependent process, the hSWI/SNF chromatin remodeling complex functions to alter chromatin structure, thereby regulating transcription factor access to DNA. In addition to interactions with transcription factors and recognition of acetylated histone residues, the chromatin remodeling activity of hSWI/SNF has also been shown to respond to a variety of cell signaling pathways. Our results demonstrate a novel interaction between the serine/threonine kinase Akt and members of the hSWI/SNF chromatin remodeling complex. Activation of Akt in HeLa cells resulted in its association with hSWI/SNF subunits: INI1, BAF155 and BAF170, as well as actin. BAF155 became preferentially recognized by an antibody that detects phosphorylated Akt substrates upon activation of Akt, suggesting that BAF155 may be an in vivo target for phosphorylation by Akt. Glutathione-S-transferase (GST) pulldown experiments demonstrated that INI1 and BAF155 were both capable of directly interacting with Akt. Finally, in vitro kinase assays provided additional evidence that BAF155 and potentially INI1 are substrates for Akt phosphorylation. These data provide the first evidence that Akt signaling may modulate function of the hSWI/SNF complex.

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p16 Is Required for hSNF5 Chromatin Remodeler-induced Cellular Senescence in Malignant Rhabdoid Tumor Cells

Cited by 154 publications

References 56 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

Role of Mdm4 in drug sensitivity of breast cancer cells

Members of the hSWI/SNF chromatin remodeling complex associate with and are phosphorylated by protein kinase B/Akt

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