Michel Faure - Academia.edu (original) (raw)

Papers by Michel Faure

Blood

We have generated a novel, fully human IgG1 anti-CD40 antagonistic monoclonal antibody, CHIR-12.1... more We have generated a novel, fully human IgG1 anti-CD40 antagonistic monoclonal antibody, CHIR-12.12, using XenoMouse® mice (Abgenix, Inc.) and have previously demonstrated that it inhibits normal human B cell proliferation and survival and has potent ADCC against primary CLL and NHL cells. CHIR-12.12 and the anti-CD20 monoclonal antibody rituximab were compared for their relative ADCC activity against a variety of malignant human B-cell lines expressing both CD40 and CD20 antigens, including two lymphoma cell lines (Daudi, Namalwa), two multiple myeloma cell lines (ARH77, IM-9), a B-ALL cell line (CCRF-SB), and a B-CLL cell line (EHEB). All cell lines expressed both CD20 and CD40 antigens, and the number of cell surface CD20 molecules per cell were 2.6- to 30.8-fold higher than CD40. For all target cell lines, despite the greater number of CD20 receptors, CHIR-12.12 showed greater maximum cell lysis and a lower ED50 than rituximab. ADCC activity of rituximab is known to correlate wit...

Cancer Research, Apr 15, 2006

Activation of the Ras-Raf-MEK-ERK pathway plays an integral role in tumor cell proliferation and ... more Activation of the Ras-Raf-MEK-ERK pathway plays an integral role in tumor cell proliferation and survival. Mutations in Ras and B-Raf have been reported in many human cancers, making these proteins attractive targets for cancer therapies. The pathway can also be activated ...

The Journal of Immunology, 2010

eLife, 2015

CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RN... more CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficientl...

Cancer Research, 2014

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The MAPK signaling cascade,... more Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The MAPK signaling cascade, comprised of the RAS GTPases, the RAF, MEK1/2 and ERK1/2 kinases is frequently deregulated in cancer. ERK1 and ERK2 transmit signals generated by mutant BRAF, Ras or by activated receptor tyrosine kinases to a wide range of nuclear and cytoplasmic substrates, resulting in signal amplification, cell growth, migration and survival. ERK1 and ERK2 have been considered as redundant because of their high homology, large number of overlapping substrates, and ability to substitute for each other in genetically engineered mouse models. Nevertheless, several investigators have identified non-redundant roles for ERK isoforms in oncogenesis; for instance, ERK2, but not ERK1, appears to be responsible for RASmut induced epithelial-to-mesenchymal transformation. Besides, each of the ERK isoforms employs spatially distinct substrate docking domains, DEF (docking site for ERK FXFP) and D (docking domain), to signal to different subsets of substrates and differentially transmit signals downstream. We set out to determine the roles of ERK isoforms as well as DEF- and D-domain dependent signaling in the survival of melanoma tumor cells expressing activating BRAF mutations which are highly sensitive to pharmacological inhibitors of RAF, MEK1/2 and ERK1/2. We designed ERK1 and ERK2 mutants resistant to ATP-competitive ERK1/2 inhibitors and employed auto-activating, MEK-independent, ERK1 and ERK2 mutants to ask if BRAFmut melanoma survival is dependent on either or both ERK isoforms. In addition, we used RNAi and zinc-finger nucleases’ to knockdown or delete each of ERK isoforms. These experimental approaches consistently demonstrated that ERK2, but not ERK1, was the sole driver of cell survival in multiple BRAFmut melanoma cell lines. Moreover, genome-wide gene expression analysis indicated that ERK2, but not ERK1, was largely responsible for transcriptional effects imposed by pharmacological RAF, MEK1/2 or ERK1/2 inhibitors. Thus, in BRAFmut melanoma, functions of ERK1 and 2 are not redundant, and ERK1 cannot substitute for a disabled ERK2. Next, we introduced DEF- and D-substrate docking domain mutations into an ERK inhibitor resistant ERK2 to investigate whether signaling through either domain is sufficient to support melanoma survival. We observed that signaling through D- or DEF- domains of ERK2 had differential effects on gene expression and substrate phosphorylation. Consequently, we have found that a subset of melanoma cell lines was sensitive to elimination of DEF- docking domain interactions, whereas another subset of cell lines tolerated mutations in the DEF-site. Interactions and signaling through ERK D-docking site were dispensable for survival of all melanoma cell lines tested. These data suggest potential novel approaches to target oncogenic MAPK pathway. Citation Format: Tatiana Zavorotinskaya, Upasana Mehra, Yumin Dai, Michel Faure, Ken Crawford, Karen Yu, Jan Marie Cheng, Xiaolei Ma, Jan Xuan, Kelly Yan, Mohammad Hekmat-Nejad, Hanne Merritt, Darrin Stuart, Charles Voliva. Dissecting MAPK pathway in BRAFmut melanoma: Intricacies of ERK1 and ERK2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-121. doi:10.1158/1538-7445.AM2014-LB-121

Molecular and cellular biology, 1989

The cyclic nucleotide phosphodiesterase (phosphodiesterase) gene plays essential roles in the dev... more The cyclic nucleotide phosphodiesterase (phosphodiesterase) gene plays essential roles in the development of Dictyostelium discoideum during cellular aggregation and postaggregation morphogenesis. Genomic clones spanning the gene were isolated and used to determine the sequence and structure of the phosphodiesterase gene. We found an unusually complex organization for a gene of D. discoideum. Two transcripts of 2.4 and 1.9 kilobases (kb) were synthesized from start sites separated by 1.1 kb. A developmentally regulated promoter was utilized for the 2.4-kb mRNA, and a constitutive promoter regulated synthesis of the 1.9-kb transcript. The gene was found to be divided into four exons that are alternately spliced to give rise to the two mRNAs. The precursor of the 2.4-kb mRNA contained a 2.3-kb intron, whereas the precursor of the constitutive transcript was synthesized with a 1.7-kb intron. The two transcripts contained identical protein-coding regions and 400-nucleotide 3' untran...

The FASEB Journal, 2009

The paper titled “Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen acti... more The paper titled “Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages,” by Wataru Matsuyama, Hidenobu Kamohara, Carole Galligan, Michel Faure, and Teizo Yoshimura published in the July 2003 issue of The FASEB Journal (17:1286-1288; doi: 10.1096/fj.02-0320fje) has been retracted at the request of the senior author, Dr. Teizo Yoshimura. Investigations carried out at Kagoshima University and by the NIH Intramural Research Integrity Office have determined that FACS data in the paper supplied by Dr. Wataru Matsuyama were falsified. These investigations held that Dr. Wataru Matsuyama was the only offender among the authors of this paper in our journal.

The FASEB Journal, 2003

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. DDR1 is c... more Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. DDR1 is constitutively expressed in a variety of normal and transformed epithelial cells and plays a role in cell migration and differentiation through as yet unidentified signaling pathways. We previously reported inducible expression of DDR1 in human leukocytes and suggested a role for the DDR1a isoform in leukocyte migration through extracellular matrix. Here, we evaluated the contribution of DDR1 in the differentiation of the human monocytic THP-1 cells overexpressing these isoforms and of primary macrophages. Interestingly, collagen activation of DDR1b, but not DDR1a, further promoted phorbol ester-induced differentiation of THP-1 cells as determined by reduced cell proliferation and up-regulated expression of HLA-DR, CD11c, CD14, and CD40. Collagen activation of DDR1b also induced the recruitment and phosphorylation of Shc and subsequent phosphorylation of p38 mitogen-activated protein (MAP) kinase and its substrate ATF2. A p38 MAP kinase inhibitor, SB203580, completely inhibited DDR1b-mediated HLA-DR expression. Activation of DDR1 endogenously expressed on macrophages also up-regulated their HLA-DR expression in a p38 MAP kinase-dependent manner. Thus, DDR1b in response to collagen transduces signals that promote maturation/differentiation of HLA-DR-positive antigen-presenting cells and contributes to the development of adaptive immunity in a tissue microenvironment.

Proceedings of the National Academy of Sciences, 1988

The Journal of Immunology, 2004

The Journal of Immunology, 2003

Journal of Biological Chemistry, 1998

Many growth factors and G protein-coupled receptors activate mitogen-activated protein (MAP) kina... more Many growth factors and G protein-coupled receptors activate mitogen-activated protein (MAP) kinase pathways. The MAP kinase pathways are involved in the regulation of the ubiquitous process of apoptosis or programmed cell death. Two related MAP kinase kinase kinases, apoptosis-signal regulating kinase 1 (ASK1) and MAP kinase kinase kinase 1 (MEKK1), stimulate c-Jun kinase (JNK) activity and induce apoptosis. Transient transfection of dominant negative and constitutively active components of the JNK pathway in COS-7 cells showed that two G protein subunits, G␣12 and G␣13, stimulated the JNK pathway in a ASK1-and MEKK1-dependent manner. Moreover, the mutationally activated G␣12 and G␣13 stimulated the kinase activity of ASK1. Both G␣12 and G␣13 employ small GTPases, Cdc42 and Rac1, to transduce signal to MEKK1 and, subsequently, to JNK. However, activation of JNK by Cdc42 and Rac1 did not require ASK1. Additionally, ASK1 and MEKK1 are involved in the apoptosis induced by G␣12 and G␣13. We conclude that G␣12 and G␣13 can induce apoptosis using two separate MAP kinase pathways; one is initiated by ASK1, and the other is initiated by MEKK1. Furthermore, Bcl-2 can block apoptosis induced by G␣12 and G␣13. This death-sparing function was associated with increased Bcl-2 phosphorylation, suggesting that phosphorylation of Bcl-2 may be a critical mechanism protecting cells from G␣12-and G␣13-induced apoptosis.

Developmental Genetics, 1988

The genes coding for the cyclic nucleotide phosphodiesterase (PD) and the PD inhibitory glycoprot... more The genes coding for the cyclic nucleotide phosphodiesterase (PD) and the PD inhibitory glycoprotein (PDI) have been cloned and characterized. The PDI gene was isolated as a 1.6 kb genomic fragment, which included the coding sequence containing two small introns and 510 nucleotides of non-translated 5' sequence. From the deduced amino acid sequence we predict a protein with a molecular weight (MW) of 26,000 that, in agreement with previous data, contains 15% cysteine residues. Genomic Southern blot analysis indicates that only one gene encodes the inhibitor. Northern blot analysis shows a single transcript of 0.95 kb. The PDI gene is expressed early in development with little transcript remaining following aggregation. The appearance of PDI mRNA is prevented by the presence of cAMP, but when cAMP is removed the transcript appears within 30 minutes. When cAMP is applied to cells expressing PDI the transcript disappears with a half-life of less than 30 minutes. The PD gene of D. discoideum is transcribed into three mRNAs: a 1.9 kb mRNA specific for growth, a 2.4 kb mRNA specific for aggregation, and a 2.2 kb mRNA specific for late development. The 2.2 kb mRNA is also specific for prestalk cells, and is induced by differentiation-inducing factor. All three mRNAs contain the same coding sequence, and differ only in their 5' non-coding sequences. Each mRNA is transcribed from a different promoter, and by using the chloramphenicol acyltransferase gene as a reporter, we have shown that each promoter displays the same regulation as its cognate mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental Biology, 1989

One of the developmentally induced gene products that is essential for chemotaxis of Dictyosteliu... more One of the developmentally induced gene products that is essential for chemotaxis of Dictyostelium amoebae is a cyclic nucleotide phosphodiesterase. The enzyme can be secreted or exist in a membrane bound form. This enzyme is missing in the mutant HPX235 which, as a consequence, does not aggregate unless exogenous cAMP phosphodiesterase is supplied. We have introduced multiple copies of the cloned phosphodiesterase gene into mutant amoebae and restored aggregation. The formation of anatomically correct fruiting bodies, which does not occur when exogenous enzyme is added, is also restored by transformation with the gene. The construct that we have used gives rise only to secreted phosphodiesterase and therefore the membrane bound form of the enzyme is not absolutely required for normal aggregation and morphogenesis.