Publications (8)30.49 Total impact
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Article: Antiproliferative and apoptotic activities of tosylcyclonovobiocic acids as potent heat shock protein 90 inhibitors in human cancer cells.
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ABSTRACT: We evaluated whether inhibition of heat shock protein 90 (hsp90) function by novobiocin derivatives could induce the degradation of signal transducers that drive cancer cell growth and thereby promote apoptosis. Removal of the noviose moiety in novobiocin and introduction of a tosyl substituent at C-4 or C-7 coumarin nucleus provided derivatives 4TCNA and 7TCNA which compared favourably with novobiocin in MCF-7 breast cancer cells. Here we extend the antiproliferative and apoptotic properties of these analogues to a panel of cancer cell lines. Destabilization of hsp90 client proteins Raf-1, HER2, and cdk4 suggests inhibition of hsp90 chaperoning function. In HT29 colon and IGROV1 ovarian cancer cells, the growth inhibiting effect of 4TCNA and 7TCNA was consistent with the stimulation of cell death as assessed by the processing and activation of caspase 9, 8, 7 and 3 and the subsequent cleavage of poly(ADP-ribose) polymerase (PARP). In Ishikawa endometrial adenocarcinoma cells, 4TCNA also promoted apoptosis and the processing of PARP. These derivatives impacting multiple pathways involved in the neoplastic process may represent promising drugs for cancer therapy.Cancer letters 11/2008; 274(1):88-94. · 4.86 Impact Factor -
Article: Reversal of glucocorticoids-dependent proopiomelanocortin gene inhibition by leukemia inhibitory factor.
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ABSTRACT: We previously have described molecular mechanisms converging at the Nur response element-signal transducer and activator of transcription (STAT) composite site responsible for synergistic activation of the proopiomelanocortin (POMC) gene promoter by leukemia inhibitory factor (LIF) and CRH. In this study, we asked how glucocorticoids (GC), the physiological negative regulators of POMC gene expression, modulate this synergism. In the corticotroph cell line AtT-20, the response of the wild-type promoter to LIF+CRH was barely inhibited by GC, whereas a distal promoter subregion (-414/-293) encompassing the Nur response element-STAT site and devoid of the negative GC-responsive element located in the proximal domain, displayed a cooperative response to LIF+dexamethasone (DEX) and LIF+CRH+DEX treatments. LIF+CRH-stimulated ACTH secretion was also inefficiently inhibited by DEX in the same cell line. This study was focused thereafter on LIF+DEX cooperativity, which may be responsible, on the wild-type promoter, for lack of negative regulation by DEX of the LIF+CRH synergy. The STAT1-3 low-affinity site, in the context of the (-414/-293) subregion of the POMC promoter, was found necessary and sufficient for transcriptional synergism between activated GC receptor (GR) and STAT1-3. Moreover the activities of reporters specific for STAT1-3 or GR were reciprocally enhanced by DEX or LIF. Single and sequential chromatin immunoprecipitations revealed 1) a STAT-dependent corecruitment of coactivators after LIF and LIF+DEX stimulation and 2) a more lasting recruitment of both STAT3 and GR in the same enhanceosome on the endogenous POMC promoter after LIF+DEX joint stimulation than after the single one. Such events may be responsible for a lack of repressive property of GR unmasked on the whole POMC promoter during LIF+CRH stimulation and may contribute to the tonicity of the hypothalamic-pituitary-adrenal axis during inflammatory-infectious diseases.Endocrinology 02/2007; 148(1):422-32. · 4.46 Impact Factor -
Article: Steroid Receptors and Effects of Oestradiol and Progesterone on Chick Oviduct Proteins
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ABSTRACT: After a single injection of oestradiol benzoate (1.5mg/kg) to oestrogen-withdrawn chickens, there was an increase in magnum wet weight, DNA polymerase α activity, adenosine-3′,5′-monophosphate-dependent protein-kinase activity and estrogen-receptor concentration, as measured over 36 h. Besides these intracellular proteins, the secretory proteins ovalbumin and conalbumin were also augmented, and detailed time-course studies were performed.Early induction kinetics for ovalbumin and conalbumin synthesis, which differed for each protein, were independent of the dose of oestradiol benzoate injected if it exceeded 0.1 mg/kg. After 6 h for ovalbumin and 2 h for conalbumin, the induction curves diverged according to the dose of hormone administered and in correlation with the persistence of elevated nuclear oestrogen-receptor concentrations, a result confirmed with 11β-methoxy-17α-ethynyloestradiol (R 2858), a powerful synthetic oestrogen.When oestradiol benzoate (1 mg/kg) and progesterone (3 mg/kg) were injected simultaneously, the rate of conalbumin synthesis, during the first 6–8 h, was lower than that observed in animals injected with oestradiol benzoate alone. However at later times conalbumin synthesis was greater in animals receiving both hormones than with oestradiol alone. In contrast, the rate of ovalbumin synthesis after the combined injection was higher than that induced by either hormone alone throughout the entire experimental period.In order to study further the synergistic and antagonistic activities of these two hormones, a single injection of progesterone (3 mg/kg) was administered 6, 12 or 18 h after 1.5 mg/kg oestradiol benzoate. Progesterone administration resulted in a reduction in cytoplasmic, nuclear and total oestrogen receptor concentration for at least 6 h when compared with the values in birds treated with oestrogen alone. DNA polymerase and protein kinase activities were also reduced during this period. Subsequently, all parameters increased, and by 18–24h after progesterone treatment, reached values higher than those observed in animals receiving oestrogen alone.European Journal of Biochemistry. 03/2005; 107(1):155 - 164. -
Article: Synergistic signaling by corticotropin-releasing hormone and leukemia inhibitory factor bridged by phosphorylated 3',5'-cyclic adenosine monophosphate response element binding protein at the Nur response element (NurRE)-signal transducers and activators of transcription (STAT) element of the proopiomelanocortin promoter.
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ABSTRACT: Leukemia inhibitory factor (LIF) cooperates with CRH at the pituitary level to induce POMC gene transcription, resulting in activation of the pituitary-adrenal axis. However, the underlying molecular mechanisms remain elusive. Here, we show that the NurRE-signal transducers and activators of transcription (STAT) composite element of the POMC promoter was the predominant target of the LIF-CRH synergy. Whereas NurRE or STAT sites alone conferred synergy, the maximal response was found with the NurRE-STAT reporter, suggesting that direct DNA binding of both transcription factors is required for an optimal synergy. During LIF-CRH stimulation, Nur77 and activated STAT1-3 were bound to the composite element, and the binding of each factor was abolished by appropriate mutations. CREB was also detected in this complex in a stimulation-dependent and DNA binding-independent manner. Nur77 and STAT1-3 bound to the NurRE-STAT site were each sufficient for CREB recruitment. Recombinant CREB directly interacted with recombinant Nur77 or STAT1-3. Moreover, CREB-Nur77 interaction was increased by CREB phosphorylation at Ser-133 and the dominant-negative mutant CREB-M1 efficiently inhibited the synergistic LIF-CRH response. This synergism was also inhibited after transfection of CREB-small interfering RNA. We conclude that both CREB phosphorylation at Ser-133 and level of CREB expression are crucial in LIF-CRH synergism where CREB, without direct DNA binding, could improve the stability of Nur77 and STAT1-3 binding to POMC promoter and facilitate the recruitment of coactivators. This novel intrapituitary signaling mechanism may have more general implications in cross talks between cAMP-protein kinase A and Janus kinase-STAT pathways.Molecular Endocrinology 01/2005; 18(12):2997-3010. · 4.54 Impact Factor -
Article: Different mechanisms for leukemia inhibitory factor-dependent activation of two proopiomelanocortin promoter regions.
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ABSTRACT: To better understand how leukemia inhibitory factor (LIF) activates proopiomelanocortin (POMC) gene transcription in pituitary corticotrophs, time-course studies of the induction of POMC promoter activity and specific tyrosine phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 were performed. It was found that both phosphorylation of STAT1 and -3 and activation of the promoter activity rapidly and transiently take place within minutes and 2-6 h, respectively, in favor of a direct effect of the LIF pathway on POMC promoter. Activated STAT1 and -3 form homo-/heterodimers able to bind the Sis-inducible element. The most abundant Sis-inducible element binding dimers are STAT3/3 and STAT1/3. Degenerated STAT1/3-binding sites from the POMC promoter were tested for their ability to bind activated STAT1 and 3; only the -390/-379 site, partially overlapping the Nur response element, binds with low affinity activated STAT1 and -3. Analysis of the three domains and subregions of the POMC promoter showed that two subregions are specifically responsive to LIF. The response of the distal subregion requires the intact STAT1 and -3 DNA-binding site -390/-379, whereas the responsiveness of the proximal subregion takes place despite the absence of direct STAT1 and -3 DNA binding and may imply interaction of activated STAT with basal transcription factors.Endocrinology 11/2002; 143(10):3916-24. · 4.46 Impact Factor -
Article: Phosphorylation of the immunosuppressant FK506-binding protein FKBP52 by casein kinase II: Regulation of HSP90-binding activity of FKBP52
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ABSTRACT: FKBP52 (HSP56, p59, HBI) is the 59-kDa immunosuppressant FK506-binding protein and has peptidyl prolyl isomerase as well as a chaperone-like activity in vitro. FKBP52 associates with the heat shock protein HSP90 and is included in the steroid hormone receptor complexes in vivo. FKBP52 possesses a well conserved phosphorylation site for casein kinase II (CK2) that was previously shown to be associated with HSP90. Here we examined whether FKBP52 is phosphorylated by CK2 both in vivo and in vitro. Recombinant rabbit FKBP52 was phosphorylated by purified CK2. We expressed and purified deletion mutants of FKBP52 to determine the site(s) phosphorylated by CK2. Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. A synthetic peptide corresponding to this region was phosphorylated by CK2, and the peptide competitively inhibited the phosphorylation of other substrates by CK2. The [32P]phosphate labeling of FKBP52-expressing cells revealed that the same site is also phosphorylated in vivo. FK506 binding to FKBP52 did not affect the phosphorylation by CK2 and, conversely, the FK506-binding activity of FKBP52 was not affected by the phosphorylation. Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90. These results indicate that CK2 phosphorylates FKBP52 both in vitro and in vivo and thus may regulate the protein composition of chaperone-containing complexes such as those of steroid receptors and certain protein kinases.Proceedings of the National Academy of Sciences 01/1998; · 9.68 Impact Factor -
Article: Effect of Tamoxifen on Oestradiol and Progesterone‐Induced Synthesis of Ovalbumin and Conalbumin in Chick Oviduct
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ABSTRACT: Tamoxifen, a non-steroidal antioestrogen, did not display any oestrogenic effects biochemically or histologically in the chick oviduct when 10 mg/kg were administered to oestrogen-withdrawn animals each day and effects were monitored during periods ranging from a few hours to 10 days.After a single injection of oestradiol benzoate, 1 mg/kg, to oestrogen-withdrawn animals, the relative rate of ovalbumin synthesis was significantly elevated by 3 h, and reached a maximum by ∼ 16 h. Conalbumin synthesis increased immediately after oestrogen administration, and attained a maximum by ∼ 16 h. Between 16 and 24 h there was a decrease of ∼ 50% in the rate of synthesis of the two proteins and in the levels of nuclear oestrogen receptor. Administration of tamoxifen together with oestradiol benzoate inhibited the oestrogen effect on ovalbumin and conalbumin synthesis. This effect of tamoxifen was dose-dependent; 50% inhibition of the maximum induction of both proteins was obtained with 1 mg of tamoxifen/kg.A series of experiments indicated that tamoxifen given after oestradiol benzoate could rapidly inhibit the oestrogenic effect, and oestradiol benzoate administered subsequent to tamoxifen could overcome the antioestrogenic effect; that is, each ligand could produce its own characteristic activity, although in both cases, at the time of administration of the second drug, the level of cytoplasmic oestrogen receptor was low.When tamoxifen was administered during the lag period of ovalbumin induction, it decreased the entire pattern of ovalbumin synthesis, but when given later, the inhibitory effect was retarded. On the other hand, the inhibition by tamoxifen of oestradiol-dependent conalbumin synthesis was virtually immediate. The basal level of conalbumin synthesis, already significant in withdrawn chickens (1%), was unaffected by tamoxifen, suggesting that endogenous oestrogens are not required to maintain this level of synthesis.Progesterone-induced increases in ovalbumin and conalbumin synthesis were not inhibited by tamoxifen. On the contrary, the simultaneous injection of tamoxifen potentiated the progesterone-increased synthesis of both proteins. These observations were supported by histological studies showing an increased accumulation of secretory granules in the magnum of chickens treated by tamoxifen plus progesterone as compared to progesterone alone.European Journal of Biochemistry. 05/1980; 107(1):165 - 172. -
Article: Estrogen-like effects of combined dexamethasone and tamoxifen in the chick oviduct
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ABSTRACT: The effects of dexamethasone alone on withdrawn chick oviduct weight, DNA, protein content and progesterone receptor concentration were barely detectable, whereas ovalbumin and conalbumin synthesis were increased. When dexamethasone and tamoxifen were combined, a marked increase of total proteins, including egg white proteins, DNA and wet weight occurred. Progesterone receptor also was increased. The most striking result was the stimulation of DNA polymerase-α activity by combined dexamethasone and tamoxifen, whereas either compound was completely ineffective.Biochemical and Biophysical Research Communications 124(1):57-62. · 2.48 Impact Factor
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Institutions
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2007
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Institut Cochin
Paris, Ile-de-France, France
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1980–2005
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Institut national de la santé et de la recherche médicale
Paris, Ile-de-France, France
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