Genomic alterations in spontaneous and carcinogen-induced murine melanoma cell lines

Melnikova, Vladislava O.; Bolshakov, Svetlana; Walker, Christopher M.; Ananthaswamy, Honnavara N.

doi:10.1038/sj.onc.1207405

Cited by 100 publications

(83 citation statements)

References 78 publications

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“…Here, we also showed that vincristine could transcriptionally regulate the mTUBB2 gene. Furthermore, although genomic alteration of the p53 gene in B16F10 cells has been reported, several studies have indicated that the p53 in these cells seems to be functional (41,42). Our results also showed that p53 protein in B16F10 cells at least retained its binding activity to the response element.…”

Section: Discussionsupporting

confidence: 74%

Regulation of Class II β-Tubulin Expression by Tumor Suppressor p53 Protein in Mouse Melanoma Cells in Response toVincaAlkaloid

Arai

Matsumoto

Nagashima

et al. 2006

Molecular Cancer Research

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The continuous exposure of antimicrotubule drugs to tumors often results in the emergence of drug-resistant tumor cells with altered expression of several B-tubulin isotypes. We found that Vinca alkaloid enhanced expression of class II B-tubulin isotype (mTUBB2) in mouse B16F10 melanoma cells via alteration of the tumor suppressor p53 protein. Vincristine treatment stimulated an increase in mTUBB2 mRNA expression and promoted accumulation of this isotype around the nuclei. Transient transfection assays employing a reporter construct, together with site-directed mutagenesis studies, suggested that the p53-binding site found in the first intron was a critical region for mTUBB2 expression. Electrophoretic mobility shift assay and associated antibody supershift experiments showed that vincristine promoted release of p53 protein from the binding site. In addition, exogenous induction of TAp63; (p51A), a homologue of p53, canceled the effect of vincristine on mTUBB2 expression. These results suggest that p53 protein may function as a suppressor of mTUBB2 expression and vincristine-mediated inhibition of p53 binding results in enhanced mTUBB2 expression. This phenomenon could be related with the emergence of drug-resistant tumor cells induced by Vinca alkaloid and may participate in determining the fate of these cells.

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Section: Discussionsupporting

confidence: 74%

Regulation of Class II β-Tubulin Expression by Tumor Suppressor p53 Protein in Mouse Melanoma Cells in Response toVincaAlkaloid

Arai

Matsumoto

Nagashima

et al. 2006

Molecular Cancer Research

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“…2). This synergy was most powerfully corroborated in mouse transgenic models in which pairwise activation and inacti vation of NRAS and CDKN2A, BRAF and PTEN, or BRAF and CDKN2A, respectively, gave rise to melanoma with high fidelity 14,15 . Characterization of tumours from large cohorts of patients with advanced-stage melanoma at the whole-genome level has provided greater granularity regarding the overall prevalence of these genetic alterations, as well as their overlap 5,9,16 (FIG.…”

Section: Genetic and Immune Landscape Of Melanomamentioning

confidence: 84%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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“…Here, we investigated the involvement of CKIs in G 1 cell-cycle arrest, and found that p27Kip1, but not p21Cip1, accumulated in B16 tumor cells following CTL therapy in vivo or IFNg treatment in vitro. Another CKI, p16, is involved in senescence-like G 1 cell-cycle arrest (14), but this factor is not expressed in B16 tumor cells due to a p16 Ink4a exon1a deletion (34). Thus, p27Kip1 appeared to be the major CKI involved in G 1 arrest in this model.…”

Section: Discussionmentioning

confidence: 97%

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

Matsushita

Hosoi

Ueha

et al. 2015

Cancer Immunology Research

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To understand global effector mechanisms of CTL therapy, we performed microarray gene expression analysis in a murine model using pmel-1 T-cell receptor (TCR) transgenic T cells as effectors and B16 melanoma cells as targets. In addition to upregulation of genes related to antigen presentation and the MHC class I pathway, and cytotoxic effector molecules, cell-cycle-promoting genes were downregulated in the tumor on days 3 and 5 after CTL transfer. To investigate the impact of CTL therapy on the cell cycle of tumor cells in situ, we generated B16 cells expressing a fluorescent ubiquitination-based cell-cycle indicator (B16-fucci) and performed CTL therapy in mice bearing B16-fucci tumors. Three days after CTL transfer, we observed diffuse infiltration of CTLs into the tumor with a large number of tumor cells arrested at the G 1 phase of the cell cycle, and the presence of spotty apoptotic or necrotic areas. Thus, tumor growth suppression was largely dependent on G 1 cell-cycle arrest rather than killing by CTLs. Neutralizing antibody to IFNg prevented both tumor growth inhibition and G 1 arrest. The mechanism of G 1 arrest involved the downregulation of S-phase kinase-associated protein 2 (Skp2) and the accumulation of its target cyclin-dependent kinase inhibitor p27 in the B16-fucci tumor cells. Because tumor-infiltrating CTLs are far fewer in number than the tumor cells, we propose that CTLs predominantly regulate tumor growth via IFNg-mediated profound cytostatic effects rather than via cytotoxicity. This dominance of G 1 arrest over other mechanisms may be widespread but not universal because IFNg sensitivity varied among tumors.

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Genomic alterations in spontaneous and carcinogen-induced murine melanoma cell lines

Cited by 100 publications

References 78 publications

Regulation of Class II β-Tubulin Expression by Tumor Suppressor p53 Protein in Mouse Melanoma Cells in Response toVincaAlkaloid

Regulation of Class II β-Tubulin Expression by Tumor Suppressor p53 Protein in Mouse Melanoma Cells in Response toVincaAlkaloid

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

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