Src family kinases promote AML cell survival through activation of signal transducers and activators of transcription (STAT)

Ozawa, Yukiyasu; Williams, Amy; Estes, Myka L.; Matsushita, Norimasa; Boschelli, Frank; Jove, Richard; List, Alan F.

doi:10.1016/j.leukres.2007.11.032

Cited by 51 publications

(37 citation statements)

References 44 publications

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“…We can now propose a molecular explanation for such a combination where these two molecules cooperate through two oncogenic survival processes, that is, DNA replication and mRNA transcription, both essential for tumor cell survival. In addition, the survival and proliferation genes CDC25A, Myc, and Src, which we identified as indirect downstream targets for triptolide, have previously been identified as important oncogenic regulators of acute myeloid leukemia (46)(47)(48). Myc has also been described to be directly involved in the tumorigenicity of ovarian, colon, and esophageal cancers (48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 81%

Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA

Vispé

DeVries

Créancier

et al. 2009

Molecular Cancer Therapeutics

157

135

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Triptolide, a natural product extracted from the Chinese plant Tripterygium wilfordii, possesses antitumor properties. Despite numerous reports showing the proapoptotic capacity and the inhibition of NF-κB-mediated transcription by triptolide, the identity of its cellular target is still unknown. To clarify its mechanism of action, we further investigated the effect of triptolide on RNA synthesis in the human non-small cell lung cancer cell line A549. Triptolide inhibited both total RNA and mRNA de novo synthesis, with the primary action being on the latter pool. We used 44K human pan-genomic DNA microarrays and identified the genes primarily affected by a short treatment with triptolide. Among the modulated genes, up to 98% are down-regulated, encompassing a large array of oncogenes including transcription factors and cell cycle regulators. We next observed that triptolide induced a rapid depletion of RPB1, the RNA polymerase II main subunit that is considered a hallmark of a transcription elongation blockage. However, we also show that triptolide does not directly interact with the RNA polymerase II complex nor does it damage DNA. We thus conclude that triptolide is an original pharmacologic inhibitor of RNA polymerase activity, affecting indirectly the transcription machinery, leading to a rapid depletion of short-lived mRNA, including transcription factors, cell cycle regulators such as CDC25A, and the oncogenes MYC and Src. Overall, the data shed light on the effect of triptolide on transcription, along with its novel potential applications in cancers, including acute myeloid leukemia, which is in part driven by the aforementioned oncogenic factors. [Mol Cancer Ther 2009;8(10):2780-90]

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Section: Discussionmentioning

confidence: 81%

Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA

Vispé

DeVries

Créancier

et al. 2009

Molecular Cancer Therapeutics

157

135

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“…Constitutive activation of STAT is associated with malignant transformation induced by various oncoproteins that are tyrosine kinases, such as Src (sarcoma viral oncogene homolog), Bcr-Abl (breakpoint cluster regionAbelson) or EGFR (epidermal growth factor receptor) (Ilaria and Van Etten 1996;Ozawa et al 2008). The target genes of STATs, such as cyclins D1/D2, Myc, Bcl-xL and Mcl-1 among others, appear to contribute to oncogenesis by activating cell cycle and inhibiting apoptosis (EplingBurnette et al 2001;Ozawa et al 2008).…”

Section: Involvement Of Stat3 In Cancermentioning

confidence: 99%

“…The target genes of STATs, such as cyclins D1/D2, Myc, Bcl-xL and Mcl-1 among others, appear to contribute to oncogenesis by activating cell cycle and inhibiting apoptosis (EplingBurnette et al 2001;Ozawa et al 2008). The constitutive activation of these transcription factors indeed generates a deregulation of growth and cell survival, invasion of tumor cells and thus the formation of metastasis, an increase in angiogenesis and suppression of immune surveillance of the tumor.…”

Section: Involvement Of Stat3 In Cancermentioning

confidence: 99%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor-and cytokine-membrane receptors including interferon and interleukin, or by nonreceptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.The family of STAT transcription factors Structure and function STAT (signal transducers and activators of transcription) proteins were originally described as a family of cytoplasmic transcription factors. In mammals, seven members of this family, each consisting of 750-900 amino acids, have been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. These transcription factors act as dimers (homo-or hetero-dimers), and their activation is dependent on their phosphorylation or via membrane receptors stimulated by either extracellular factors, including interferon (IFN) and interleukin (IL-6), or by intracellular kinases independent of receptors, including Src. Activation of STATs is usually transient and highly regulated. STAT proteins contain seven conserved structural and functional domains ( First, the amino terminal NH 2 domain is involved in the dimerization of STAT proteins and in the stabilization of the interaction established between these dimers and DNA response elements (Braunstein et al. 2003;Mertens et al. 2006). The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al. 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes. With the exception of STAT2, all activated STAT homodimers bind directly to a palindromic sequence, the GAS (IFN-gammaactivated site), TTTCCNGGAAA (Becker et al. 1998). The ''linker'' domain localizes the active dimer to the DNA binding site. The transcriptional activation domain (TAD) contains sites of phosphorylation of serine residues that allow the recruitment of coactivators such as RNA polymerase II, histone acetyltransferase (HAT) (Paulson et al. 2002), histone deacetylase (HDAC) (Rascle et al. 2003) and chromatin modification complexes.Finally, two sites are particularly critical for the activity of STAT. These are the SH2 domain (Src homology 2, amino acids 575-680), which is linked to the DBD by the linker domain, and a conser...

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“…There are a multitude of Src kinase inhibitors in development to address the causative role of Src in solid tumours (Puls et al, 2011) but its involvement in AML deserves further investigation. The role for Src in promoting the proliferation of AML blasts has already been established (Ozawa et al, 2008), as has its position as a mediator of FLT3-ITD signalling (Leischner et al, 2012;Robinson et al, 2005) and TK inhibitors which target Src have already progressed through clinical trials for the treatment of CML (Schenone et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

Corcoran

Cotter

2012

Free Radical Research

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Access to the full text of the published version may require a subscription. and ideas for this work, and who supported and believed in me throughout -I am grateful to have had the opportunity to learn from the best. I must also give a huge thank you to Kate Cotter, who made me feel at home from day one, and who has continued to be a tireless source of energy and assistance. RightsI was fortunate to interact with a vibrant, dynamic group in the Cotter Lab and I owe a huge thanks to every single member, past-Claire, Ruth, Carolyn, Chris, Ashley, To all the friends that I have made in U.C.C. and beyond during this process, as well as those friends lucky enough not to be involved but who still got to listen to all that whingeing-thank you! Lastly, I am most indebted to those closest to me. My mam -who is always ready to listen, comfort and reassure, and as a result probably knows more than she ever wanted to about cells and reactive oxygen species! My dad, a real scientist, who never stops teaching and never stops learning, and is still the person I turn to with my "homework" questions! I am so grateful to you both for your wisdom, encouragement and patience; truly I could not have achieved this without you. ToSinead and Dara, for all the much needed distractions and laughs, and for even being interested! And to John, for being there throughout, for the joy and the inspiration. To everyone still waiting for good news or the right medicine 'Happy is he who gets to know the reasons for things.' -Virgil DeclarationThis thesis has not been submitted in whole or in part to this or any other university for any degree and is, unless otherwise stated, the original work of the author. pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to iii NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study.The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalli...

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Src family kinases promote AML cell survival through activation of signal transducers and activators of transcription (STAT)

Cited by 51 publications

References 44 publications

Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA

Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

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