STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress

Uckun, Fatih M.; Qazi, Sanjive; Ma, Hong; Tuel‐Ahlgren, Lisa; Ozer, Zahide

doi:10.1073/pnas.0909086107

Cited by 87 publications

(140 citation statements)

References 57 publications

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“…It has been reported that STAT3 is activated by oxidative stress. 45 To evaluate the oxidative stress induced by mutant IDH1, we measured ROS accumulation in mutant IDH-expressing clones, but were unable to detect any significant increase of ROS. It is possible that 2HG may modulate the oxidative state of specific metabolites, which were not detectable under the conditions we used.…”

Section: Discussionmentioning

confidence: 99%

Mutant IDH1 Confers an in Vivo Growth in a Melanoma Cell Line with BRAF Mutation

Shibata¹,

Kokubu²,

Miyamoto³

et al. 2011

The American Journal of Pathology

117

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Melanoma is the most deadly tumor of the skin, and systemic therapies for the advanced stage are still limited. Recent genetic analyses have revealed the molecular diversity of melanoma and potential therapeutic targets. By screening a cohort of 142 primary nonepithelial tumors, we discovered that about 10% of melanoma cases (4/39) harbored an IDH1 or IDH2 mutation. These mutations were found to coexist with BRAF or KIT mutation, and all IDH1 mutations were detected in metastatic lesions. BRAF-mutated melanoma cells, additionally expressing the cancer-related IDH1 mutant, acquired increased colony-forming and in vivo growth activities and showed enhanced activation of the MAPK and STAT3 pathways. Genome-wide gene expression profiling demonstrated that mutant IDH1 affected the expression of a set of genes. Especially, it caused the induction of growth-related transcriptional regulators (Jun, N-myc, Atf3) and the reduction of Rassf1 and two dehydrogenase genes (Dhrs1 and Adh5), which may be involved in the carcinogenesis of IDH1-mutated tumors. Our analyses demonstrate that IDH1 mutation works with other oncogenic mutations and could contribute to the metastasis in melanoma. Melanoma is the most malignant tumor of the skin, and the median survival rate of patients with metastatic tumors is less than 1 year.1 Although the incidence of melanoma has been increasing around the world, systemic therapies for the advanced stage are still limited. 2Recent studies have provided a clearer picture of the molecular events leading to melanoma development and progression.3,4 Since the identification of prevalent activating mutations of BRAF kinase, 5 further molecular studies have clarified the role of this pathway and others in melanomagenesis. 6 Recent genetic investigations have also demonstrated specific genotype-phenotype correlations that would be potentially informative in the context of the molecular subclassification of melanoma and therapeutic target molecules.7 For example, the c-kit gene mutations have been frequently reported in acral lentiginous/mucosal melanomas and are associated with better responsiveness to the inhibitor, imatinib. -10Recently, unbiased whole-exon resequencing analysis of glioblastoma multiforme has revealed recurrent mutation of the two IDH (isocitrate dehydrogenase) isoforms, IDH1 and IDH2.11 Subsequent analysis showed that these mutations are frequent in glioma and associated with better prognosis 12,13 ; furthermore, they have also been detected in a subset (about 8% to 16%) of acute myeloid leukemia (AML).14 -17 These enzymes convert isocitrate to ␣-ketoglutarate (␣-KG) with concurrent reduction of NADPH, but IDH1 is localized in the cytosol 18 whereas IDH2 is localized in mitochondria. 19 Mutations of the two genes affect the residues responsible for hydrophilic interactions with the substrate, and have been shown to impair the enzymatic activity, and therefore they are considered to be loss-of-function alleles.12 However, because the mutations are clustered in specific residues and only...

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Section: Discussionmentioning

confidence: 99%

Mutant IDH1 Confers an in Vivo Growth in a Melanoma Cell Line with BRAF Mutation

Shibata¹,

Kokubu²,

Miyamoto³

et al. 2011

The American Journal of Pathology

117

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“…However, further studies are required to examine specific signaling pathways that are affected by increased mitochondrial superoxide. It would be predicted that redox-sensitive signaling cascades such as NF-κB [17], AP-1 [15], or JAK/STAT [18] may be affected and, as such, may in part in explaining the pseudo-activated state and microarray results observed in this study. Furthermore, the role of posttranslational modifications on proteins such as the hypoxia-inducible factor could also provide valuable information on how ROS regulate cellular signaling [62].…”

Section: Discussionmentioning

confidence: 77%

“…More recently it has been shown that cells possess the ability to exploit ROS for signaling and functional purposes. For example, many transcription factor pathways are sensitive to oxidative stress and as such are able to help cells adapt to large deviations in redox status [15][16][17][18]. Moreover, ROS are essential in the development of certain organ systems and even whole organisms [19,20].…”

Section: Author Contributionsmentioning

confidence: 99%

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Epigenetic Control of Prolyl and Asparaginyl Hydroxylases in Prostate Cancer

Case¹

2011

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT TYPE 3. DATES COVERED (From -To) 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail:5f. WORK UNIT NUMBER In many solid tumors, including prostate cancer, hypoxia-inducible factors (HIF) are up-regulated compared to their normal tissue counterparts. These HIF molecules are transcription factors, and up-regulate metabolic and angiogenic proteins in the cancer. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTRecently, a set of proteins known as prolyl and asparaginyl hydroxylases (PHD and AHD respectively) have been shown to be essential in the regulation of HIF, and in some cancers have been transcriptionally and translationally silenced. We therefore proposed a study that focuses on the epigenetic control of these crucial enzymes. In this report, we present data demonstrating our first findings of PHD expression in prostate cancer cell lines as well as expanding our studies to relevant human samples.Furthermore, we begin to identify specific epigenetic mechanisms that may play a major role in the transcriptional and translational control of these enzymes. Last, we will explain our future direction of the project after the award period has expired. hydroxylases (PHD and AHD respectively) have been shown to be essential in the regulation of HIF, and in some cancers have been transcriptionally and translationally silenced. We therefore proposed a study that focuses on the epigenetic control of these crucial enzymes. In this report, we present data demonstrating our first findings of PHD expression in prostate cancer cell lines as well as expanding our studies to relevant human samples. Furthermore, we begin to identify specific epigenetic mechanisms that may play a major role in the transcriptional and translational...

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“…Intact SH2 and PH domains are required for a full recovery of Btk-mediated oxidative stress-induced intracellular calcium mobilization, although mutation of the SH2 (Arg307 to Ala) or PH (Arg28 to Cys) domain did not affect the oxidative stress-induced activation of Btk. Interestingly, Syk SH2 domains play different roles on substrate selectivity as Syk SH2 domains has no effect on oxidative stressinduced phosphorylation of STAT3 [30] . The overall results demonstrate that functional SH2 and PH domains are required for Btk to form a complex with PLCγ2 through BLNK in order to position the Btk, PLCγ2, and phosphatidylinositol 4,5-bisphosphate in close proximity for efficient activation of PLCγ2 and to maximize its catalytic efficiency for IP3 production [29] .…”

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confidence: 99%

Suofu Qin’s work on studies of cell survival signaling in cancer and epithelial cells

Qin¹

2010

WJBC

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Reactive oxygen species (ROS) encompass a variety of diverse chemical species including superoxide anions, hydrogen peroxide, hydroxyl radicals and peroxynitrite, which are mainly produced via mitochondrial oxidative metabolism, enzymatic reactions, and light-initiated lipid peroxidation. Over-production of ROS and/or decrease in the antioxidant capacity cause cells to undergo oxidative stress that damages cellular macromolecules such as proteins, lipids, and DNA. Oxidative stress is associated with ageing and the development of agerelated diseases such as cancer and age-related macular degeneration. ROS activate signaling pathways that promote cell survival or lead to cell death, depending on the source and site of ROS production, the specific ROS generated, the concentration and kinetics of ROS generation, and the cell types being challenged. However, how the nature and compartmentalization of ROS contribute to the pathogenesis of individual diseases is poorly understood. Consequently, it is crucial to gain a comprehensive understanding of the molecular bases of cell oxidative stress signaling, which will then provide novel therapeutic opportunities to interfere with disease progression via targeting specific signaling pathways. Currently, Dr. Qin's work is focused on inflammatory and oxidative stress responses using the retinal pigment epithelial (RPE) cells as a model. The study of RPE cell inflammatory and oxidative stress responses has successfully led to a better understanding of RPE cell biology and identification of potential therapeutic targets.

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STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress

Cited by 87 publications

References 57 publications

Mutant IDH1 Confers an in Vivo Growth in a Melanoma Cell Line with BRAF Mutation

Mutant IDH1 Confers an in Vivo Growth in a Melanoma Cell Line with BRAF Mutation

Epigenetic Control of Prolyl and Asparaginyl Hydroxylases in Prostate Cancer

Suofu Qin’s work on studies of cell survival signaling in cancer and epithelial cells

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