Pharmacological Inhibition of BMK1 Suppresses Tumor Growth through Promyelocytic Leukemia Protein

Yang, Qingkai; Deng, Xianming; Lu, Bingwen; Cameron, Michael D.; Fearns, Colleen; Patricelli, Matthew P.; Yates, John R.; Gray, Nathanael S.; Lee, Jiing-Dwan

doi:10.1016/j.ccr.2010.08.008

Cited by 177 publications

(233 citation statements)

References 45 publications

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“…Cells were maintained in DMEM with 10% FBS in the presence or absence of HSYA at the indicated concentrations for the indicated times. To determine whether the ERK5 signaling pathway is involved in the inhibitive effect of HSYA on HSC activation, XMD 8-92 (5 mM), a selective inhibitor of ERK5, was used, which was added to cell cultures 30 min before treatment with HSYA (Yang et al, 2010). Control HSC was treated with the appropriate amount of sterile pyrogen-free water.…”

Section: Treatment Of Cellsmentioning

confidence: 99%

Alteration of the ERK5 pathway by hydroxysafflor yellow A blocks expression of MEF2C in activated hepatic stellate cellsin vitro: Potential treatment for hepatic fibrogenesis

Dong

Liu

Zou

et al. 2013

Pharmaceutical Biology

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Section: Treatment Of Cellsmentioning

confidence: 99%

Alteration of the ERK5 pathway by hydroxysafflor yellow A blocks expression of MEF2C in activated hepatic stellate cellsin vitro: Potential treatment for hepatic fibrogenesis

Dong

Liu

Zou

et al. 2013

Pharmaceutical Biology

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“…14 The tumourigenicity of Erk5 has been related to its capacity to interact with promyelocytic leukemia protein and inhibit its tumor suppressor activity. 15 By blocking the interaction of promyelocytic leukemia protein and MDM2 Erk5 allows the inhibition of tumor suppressor p53 by MDM2. 16 In the cell, nucleotide metabolism is controlled by 2 pathways: the de novo and salvage pathways.…”

Section: Introductionmentioning

confidence: 99%

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

et al. 2015

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An adequate supply of nucleotides is essential for accurate DNA replication, and inappropriate deoxyribonucleotide triphosphate (dNTP) concentrations can lead to replication stress, a common source of DNA damage, genomic instability and tumourigenesis. Here, we provide evidence that Erk5 is necessary for correct nucleotide supply during erythroid development. Mice with Erk5 knockout in the haematopoietic lineage showed impaired erythroid development in bone marrow, accompanied by altered dNTP levels and increased DNA mutagenesis in erythroid progenitors as detected by exome sequencing. Moreover, Erk5-depleted leukemic Jurkat cells presented a marked sensitivity to thymidine-induced S phase stalling, as evidenced by increased H2AX phosphorylation and apoptosis. The increase in thymidine sensitivity correlated with a higher dTTP/dCTP ratio. These results indicate that Erk5 is necessary to maintain the balance of nucleotide levels, thus preventing dNTP misincorporation and DNA damage in proliferative erythroid progenitors and leukemic Jurkat T cells.

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“…23,24 Moreover, restoration of PML expression has been shown to attenuate tumor development in a xenograft model. 51,52 Our findings provide a rationale for targeting the E6AP-PML axis for treating B-cell lymphomas by triggering PML-mediated cellular senescence. This is of particular interest, given that PML expression is downregulated in a variety of human cancers, including NHL, and that this occurs largely at the protein level.…”

Section: Discussionmentioning

confidence: 99%

E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis

Wolyniec

Shortt

Stanchina

et al. 2012

Blood

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IntroductionA link between proteasomal degradation and cancer development has been established and a general proteasome inhibitor, Velcade (bortezomib), is in clinical use for the treatment of multiple myeloma and mantle cell lymphoma. 1,2 Deregulation of E3 ubiquitin ligases can be sufficient to suppress the expression and function of key tumor suppressors. For example, the inhibition of p53 as a consequence of Mdm2 amplification is frequently observed in human sarcomas and retinoblastoma. [3][4][5] Interestingly, in human papilloma virus (HPV)-infected cells the suppression of p53 is not achieved by Mdm2, but rather by the cellular E6AP (E6-associated protein) ubiquitin ligase, which is recruited to p53 by the HPV-E6 protein. [6][7][8] E6AP is encoded by the UBE3A locus, which is mutated in Angelman syndrome (AS), a human neuro-developmental disorder. 9 E6AP was the first mammalian ubiquitin E3 ligase to be identified. It is the prototype of the subfamily of E3 ligases that covalently bind ubiquitin and are characterized by a C-terminal HECT (homologous to the E6AP C terminus) domain. 10 We recently demonstrated that E6AP regulates the stability of the promyelocytic leukemia (PML) protein and the formation of PML nuclear bodies (PML-NBs). 11 PML is a tumor suppressor that was identified as a consequence of the chromosomal translocation of its gene in acute promyelocytic leukemia (APL). 12 Consistent with the role of PML as a tumor suppressor, PML deficient mice showed abnormally increased susceptibility to carcinogen 13,14 and oncogene-induced tumorigenesis. 15 Importantly, PML expression was found to be down-regulated or lost in a variety of human cancer types, including prostate, breast, and colon adenocarcinomas. 16,17 PML protein and the PML-NBs were found to play critical roles in cellular stress responses, including those that elicit apoptosis or cellular senescence. 18-21 Cellular senescence is emerging as an important mechanism for tumor suppression. 22,23 It represents a profound arrest of cellular proliferation, accompanied by a distinct set of alterations in the cellular phenotype, such as the formation of senescence-associated heterochromatin foci (SAHF, eg, H3K9me3) and up-regulation of certain inhibitors of cell growth, such as p21, PAI-1, and p16. 24 In this study, we explored the role of the E6AP-PML axis in HPV-independent cancer development. We chose pre-B/B-cell lymphomagenesis as a model For personal use only. on May 7, 2018. by guest www.bloodjournal.org From because of the high frequency of PML down-regulation in nonHodgkin lymphomas (NHLs). 16 For this purpose we used the well established E-myc transgenic mice, a mouse model for Burkitt lymphoma and other NHLs. 25 We found that the loss of one allele of E6AP significantly delayed Myc-driven B-cell lymphomagenesis and this was accompanied by elevated PML expression and the induction of cellular senescence. Importantly, E6AP expression was observed to be elevated in human Burkitt lymphoma and cell lines derived from these tumors. Our findi...

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Pharmacological Inhibition of BMK1 Suppresses Tumor Growth through Promyelocytic Leukemia Protein

Cited by 177 publications

References 45 publications

Alteration of the ERK5 pathway by hydroxysafflor yellow A blocks expression of MEF2C in activated hepatic stellate cellsin vitro: Potential treatment for hepatic fibrogenesis

Alteration of the ERK5 pathway by hydroxysafflor yellow A blocks expression of MEF2C in activated hepatic stellate cellsin vitro: Potential treatment for hepatic fibrogenesis

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis

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