Myeloblastin is a granulocyte colony-stimulating factor-responsive gene conferring factor-independent growth to hematopoietic cells

Lutz, Pierre G.; Moog-Lutz, Christel; Coumau-Gatbois, Edith; Kobari, Ladan; Gioia, Yolande Di; Cayre, Yvon E.

doi:10.1073/pnas.97.4.1601

Cited by 40 publications

(39 citation statements)

References 46 publications

(35 reference statements)

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“…This cell line is a murine bone marrow-derived pro-B-cell line that depends on interleukin-3 (IL-3) for proliferation, but readily becomes IL3-independent in the presence of an oncogene or oncogenic event. Thus, the Ba/F3 cells represent a sensitive tool for measuring the effect of an introduced perturbation on cell proliferation and survival, not only for kinase genes but also non-kinase genes (Lutz et al 2000;Warmuth et al 2007;Yoda et al 2010;Cheung et al 2011).…”

Section: Novel Driver Cancer Genes In Endometrial Cancermentioning

confidence: 99%

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

et al. 2012

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Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the ''sensor'' cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.

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Section: Novel Driver Cancer Genes In Endometrial Cancermentioning

confidence: 99%

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

et al. 2012

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“…It is down-regulated during both normal myelopoiesis and the differentiation of human promyelocytic leukemia cell lines treated with different differentiation inducers (Bories et al, 1989;Labbaye et al, 1993;Zimber et al, 2000). Recently, it was demonstrated that the PR3 gene is a granulocyte colony-stimulating factor-responsive gene conferring factor-independent growth to hematopoietic cells (Lutz et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Gordon

Rastegar

et al. 2002

Oncogene

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We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (DC m ) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001 -0.01 mM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3-and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells.

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“…In another area of research focusing on myelopoietic mechanisms, PR3 (also termed myeloblastin) was described as a myeloid-specific serine protease (9). PR3 is expressed in human progenitor CD34 ϩ cells at the mRNA and protein levels and appears to be up-regulated by the granulocyte colonystimulating factor (G-CSF) (10).…”

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confidence: 99%

Cleavage of p21 by Proteinase-3, a Myeloid-specific Serine Protease, Potentiates Cell Proliferation

Witko‐Sarsat

Canteloup

Durant

et al. 2002

Journal of Biological Chemistry

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In this study, we present evidence for the critical role of proteinase-3 (PR3) in the proliferation of myeloid cells via the proteolytic regulation of the cyclin-dependent kinase inhibitor p21 waf1 . Expression of recombinant PR3 in rat (RBL) or human (HMC1) mast cell lines increased bromodeoxyuridine incorporation and CDK2 activity compared with RBL and HMC1 cells transfected with an enzymatically inactive PR3 mutant (PR3(S203A)) or with human neutrophil elastase. Western blot analysis of p21 waf1 showed an absence of detectable protein, despite normal levels of p21 mRNA. Ectopic overexpression of p21 restored normal levels of p21 in the RBL/PR3/p21 double transfectants and reverted the proliferative effect of PR3. Inhibition of the 26 S proteasome by lactacystin or of caspases by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone did not inhibit p21 proteolysis. p21 cleavage correlated with PR3 expression in HMC1 cells infected with recombinant adenoviral vector Ad/PR3. During in vitro studies, purified p21 was cleaved by PR3, resulting in a 10-kDa p21 fragment. Employing double immunofluorescence confocal microscopy, subcellular fractionation, and coimmunoprecipitation, we found that PR3 and p21 colocalized in the cytosol. In human neutrophils treated with tumor necrosis factor-␣, which induces PR3 reexpression, we observed that p21 disappeared and was reversed by Pefabloc, a serine proteinase inhibitor. The physiopathological implications of the cleavage of p21 by PR3 have to be determined.Myeloid cells express several lineage-specific proteinases in the course of their differentiation and store them in granular pools. As a result, mature phagocytes are equipped with a large assortment of proteinases that play a key role in the noxious potential to pathogens or host tissues (1, 2). We hypothesized that a redundancy in serine proteinase activities might be important for mediating various regulatory functions in myeloid cell differentiation as well as in mature phagocytes, including, but not restricted to, microbicidal activity. We also assumed that each serine proteinase could have a unique substrate specificity. Proteinase-3 (PR3) 1 and human neutrophil elastase (HNE) belong to the myeloid serine proteinase family, which also includes cathepsin G and azurocidin, which are implicated in the destruction of microorganisms and extracellular matrix degradation (3). Although PR3 shares the highest sequence homology with HNE (60%) and has a similar substrate specificity, PR3 has some very special properties that are distinct from those of HNE (4). First, the subcellular localization of PR3 is not restricted to the azurophil granule compartment, but its membrane-associated form is also localized in secretory vesicles, thus leading to plasma membrane expression upon very mild neutrophil stimulation (5). Second, in contrast to all other proteins from azurophil granules whose biosynthesis is restricted to the promyelocytic stage, PR3 mRNA is re-expressed in vitro in both mature neutrophils and monocytes after tumor necr...

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Myeloblastin is a granulocyte colony-stimulating factor-responsive gene conferring factor-independent growth to hematopoietic cells

Cited by 40 publications

References 46 publications

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Cleavage of p21 by Proteinase-3, a Myeloid-specific Serine Protease, Potentiates Cell Proliferation

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