Changes in leukocyte gene expression profiles induced by antineoplastic chemotherapy

González-Fernández, Rebeca; Morales, Manuel; Ávila, Julio; Martín‐Vasallo, Pablo

doi:10.3892/ol.2012.669

Cited by 13 publications

(9 citation statements)

References 34 publications

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“…These results are consistent with previous studies that have shown transcriptional effects of taxanes independently of microtubule formation (22, 23). For example, we found that nab-paclitaxel treatment results in increased expression of IL1β , which encodes a pro-inflammatory cytokine.…”

Section: Discussionsupporting

confidence: 94%

Gene expression of peripheral blood cells reveals pathways downstream of glucocorticoid receptor antagonism and nab-paclitaxel treatment

Maranville

Nanda

Fleming

et al. 2014

Pharmacogenetics and Genomics

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Objectives While paclitaxel treatment is associated with leukopenia, the mechanisms that underlie this effect are not well-characterized. Additionally, despite the importance of glucocorticoid signaling in cancer treatment, the genomic effects of glucocorticoid receptor (GR) antagonism by mifepristone treatment in primary human cells have never been described. Methods As part of a randomized Phase 1 clinical trial, we used microarrays to profile gene expression in peripheral blood cells sampled from each of 4 patients at baseline, after placebo/nab-paclitaxel treatment (cycle 1), and after mifepristone/nab-paclitaxel treatment (cycle 2). Results We found that 63 genes were differentially-expressed following treatment with nab-paclitaxel, including multiple genes in the tubulin pathway. We also found 606 genes that were differentially expressed in response to mifepristone; genes down-regulated by mifepristone overlapped significantly with those previously identified as being up-regulated by dexamethasone. Conclusions These results provide insights into the mechanisms of paclitaxel and GR inhibition in peripheral blood cells.

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Section: Discussionsupporting

confidence: 94%

Gene expression of peripheral blood cells reveals pathways downstream of glucocorticoid receptor antagonism and nab-paclitaxel treatment

Maranville

Nanda

Fleming

et al. 2014

Pharmacogenetics and Genomics

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“…It is one of the most common auto-antigens present in inflammatory myopathies, with one fourth of juvenile dermatomyositis (DM) patients being found positive for anti-MORC3 antibodies (Gunawardena et al, 2009). Recent clinical studies reveal elevated MORC3 expression in leukocytes following anti-cancer chemotherapy (Gonzalez-Fernandez et al, 2012). MORC3 localizes to promyelocytic leukemia nuclear bodies (PML-NBs), where it regulates p53 activity essential for cellular senescence in human and mouse fibroblasts (Mimura et al, 2010; Takahashi et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase

Andrews

Tong

Sullivan³

et al. 2016

Cell Reports

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MORC3 is linked to inflammatory myopathies and cancer, however the precise role of MORC3 in normal cell physiology and disease remains poorly understood. Here, we present detailed genetic, biochemical, and structural analyses of MORC3. We demonstrate that MORC3 is significantly upregulated in Down syndrome, and that genetic abnormalities in MORC3 are associated with cancer. The CW domain of MORC3 binds to the methylated histone H3K4 tail, and this interaction is essential for the recruitment of MORC3 to chromatin and accumulation in nuclear bodies. We show that MORC3 possesses intrinsic ATPase activity that requires DNA however is negatively regulated by CW, which interacts with the ATPase domain. Natively linked CW impedes binding of the ATPase domain to DNA, resulting in a decrease in the DNA-stimulated enzymatic activity. Collectively, our studies provide a molecular framework detailing newly identified functions of MORC3 and suggest that its modulation may contribute to human disease.

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“…MORC3 | ATPase | CW | histone | chromatin M icrorchidia 3 (MORC3) is a member of a new family of human ATPases. Originally identified as an autoantigen in inflammatory myopathies (1)(2)(3), it has since been linked to other autoimmune disorders, Down syndrome, and cancer (4)(5)(6)(7). Studies using mouse models show that knockout of Morc3 is perinatally lethal, and partial loss of Morc3 results in changes in bone calcium homeostasis and up-regulation of inflammatory pathways (8).…”

mentioning

confidence: 99%

Mechanism for autoinhibition and activation of the MORC3 ATPase

Zhang

Klein

Cox

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Microrchidia 3 (MORC3) is a human protein linked to autoimmune disorders, Down syndrome, and cancer. It is a member of a newly identified family of human ATPases with an uncharacterized mechanism of action. Here, we elucidate the molecular basis for inhibition and activation of MORC3. The crystal structure of the MORC3 region encompassing the ATPase and CW domains in complex with a nonhydrolyzable ATP analog demonstrates that the two domains are directly coupled. The extensive ATPase:CW interface stabilizes the protein fold but inhibits the catalytic activity of MORC3. Enzymatic, NMR, mutational, and biochemical analyses show that in the autoinhibited, off state, the CW domain sterically impedes binding of the ATPase domain to DNA, which in turn is required for the catalytic activity. MORC3 autoinhibition is released by disrupting the intramolecular ATPase:CW coupling through the competitive interaction of CW with histone H3 tail or by mutating the interfacial residues. Binding of CW to H3 leads to a marked rearrangement in the ATPase–CW cassette, which frees the DNA-binding site in active MORC3 (on state). We show that ATP-induced dimerization of the ATPase domain is strictly required for the catalytic activity and that the dimeric form of ATPase–CW might cooperatively bind to dsDNA. Together, our findings uncovered a mechanism underlying the fine-tuned regulation of the catalytic domain of MORC3 by the epigenetic reader, CW.

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Changes in leukocyte gene expression profiles induced by antineoplastic chemotherapy

Cited by 13 publications

References 34 publications

Gene expression of peripheral blood cells reveals pathways downstream of glucocorticoid receptor antagonism and nab-paclitaxel treatment

Gene expression of peripheral blood cells reveals pathways downstream of glucocorticoid receptor antagonism and nab-paclitaxel treatment

Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase

Mechanism for autoinhibition and activation of the MORC3 ATPase

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