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Biomedical subjects

Bernard Haye

Publications and source records attributed to Bernard Haye.

8 recordsLinked to original sources

Elastin as a matrikine.

The fact that elastin peptides, the degradation products of the extracellular matrix protein elastin, are chemotactic for numerous cell types, promote cell cycle progression and induce release of proteolytic enzymes by stromal and cancer cells, strongly suggests that their presence in tissues could contribute to tumour progression. Thus, elastin peptides qualify as matrikines, i.e. peptides originating from the fragmentation of matrix proteins and presenting biological activities. After a brief description of their origin, the biological activities of these peptides are reviewed, emphasising their potential role in cancer. The nature of their receptor and the signalling events it controls are also discussed. Finally, the structural selectivity of the elastin complex receptor is presented, leading to the concept of elastokine (matrikine originating from elastin fragmentation) and morpho-elastokine, i.e. peptides presenting a conformation similar to that of bioactive elastin peptides and mimicking their effects.

Elastin↗

TIMPs as multifacial proteins.

Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs) found in most tissues and body fluids. By inhibiting MMPs activities, they participate in tissue remodeling of the extracellular matrix (ECM). The balance between MMPs and TIMPs activities is involved in both normal and pathological events such as wound healing, tissue remodeling, angiogenesis, invasion, tumorigenesis and metastasis. The intracellular signalling controlling both TIMPs and MMPs expression begins to be elucidated and gaining insights into the molecular mechanisms regulated by TIMPs and MMPs could represent a new approach in the development of potential therapeutics. Numerous investigations have pointed out that TIMPs exhibit multifunctional activities distinct from MMP inhibition. In this review, we detailed the multiple activities of TIMPs in vivo and in vitro and we reported their implication in physiological and pathological processes. Further, we documented recent studies of their role in hematopoiesis and we itemized the different signalling pathways they induced.

Animals↗

Functional role of nicotinic acetylcholine receptors in apoptosis in HL-60 cell line.

The subunit composition of nicotinic acetylcholine receptors involved in apoptosis is an ongoing question. HL-60 cells were used in order to investigate the implication of nicotinic acetylcholine receptors in bleomycin-induced apoptosis. We found that bleomycin-induced apoptosis was significantly enhanced by nicotine and was blocked by nicotinic acetylcholine receptor antagonists, including alpha-bungarotoxin, a competitive antagonist of alpha 7 nicotinic receptor. Among the other agonists tested, 3-[2,4-dimethoxybenzylidene]anabaseine (GTS-21)-selective agonist for alpha 7-nicotinic acetylcholine receptor-, but not epibatidine or cytisine, enhanced bleomycin-induced apoptosis. In addition to these results, the detectable presence of alpha 7-mRNA supports a key role of alpha 7-nicotinic acetylcholine receptors in the modulation of the induced apoptosis by nicotine.

Apoptosis↗

Tissue inhibitor of metalloproteinases-1 signalling pathway leading to erythroid cell survival.

Tissue inhibitors of metalloproteinases (TIMP) are specific inhibitors of matrix metalloproteinases (MMPs) and thus participate in maintaining the balance between extracellular matrix deposition and degradation in several physio-pathological processes. Nevertheless, TIMP must be regarded as multifunctional proteins involved in cell growth, angiogenesis and apoptosis. The molecular mechanisms induced by TIMP remain largely unknown. In the present study, we provide evidence that TIMP-1 induces a significant anti-apoptotic effect in the human erythroleukaemic cell line UT-7 and in the murine myeloid cell line 32D. Using specific kinases inhibitors, we show that TIMP-1-mediated cell survival is dependent upon Janus kinase (JAK) 2 and phosphoinositide 3-kinase (PI 3-kinase) activities. By transient transfection of dominant-negative Akt in UT-7 cells, we demonstrate that this kinase is crucial for the TIMP-1 anti-apoptotic effect. Moreover, TIMP-1 enhances specific phosphorylation of both Akt and Bad (Bcl-2/Bcl-X(L)-antagonist, causing cell death) in a PI 3-kinase-dependent manner and, besides, controls the level of the anti-apoptotic protein Bcl-X(L). We conclude that TIMP-1 induces haematopoietic cell survival via the JAK2/PI 3-kinase/Akt/Bad pathway.

Animals↗

Involvement of the Src kinase Lyn in phospholipase C-gamma 2 phosphorylation and phosphatidylinositol 3-kinase activation in Epo signalling.

We examined the role of the Src kinase Lyn in phospholipase C-gamma 2 (PLC-gamma 2) and phosphatidylinositol (PI) 3-kinase activation in erythropoietin (Epo)-stimulated FDC-P1 cells transfected with a wild type (WT) Epo-receptor (Epo-R). We showed that two inhibitors of Src kinases, PP1 and PP2, abolish both PLC-gamma 2 tyrosine phosphorylation and PI 3-kinase activity in WT Epo-R FDC-P1 cells. We also demonstrated that Epo-phosphorylated Lyn is associated with tyrosine phosphorylated PLC-gamma 2 and PI 3-kinase in WT Epo-R FDC-P1-stimulated cells. Moreover Epo-activated Lyn phosphorylates in vitro PLC-gamma 2 immunoprecipitated from unstimulated cells. Our results suggest that the Src kinase Lyn is involved in PLC-gamma 2 phosphorylation and PI 3-kinase activation induced by Epo.

Animals↗

The elastin peptides-mediated induction of pro-collagenase-1 production by human fibroblasts involves activation of MEK/ERK pathway via PKA- and PI(3)K-dependent signaling.

Elastin peptides, such as kappa-elastin (kE), bind to the elastin receptor at the cell surface of human dermal fibroblasts and stimulate collagenase-1 expression at the gene and protein levels. Using specific inhibitors and phosphospecific antibodies, we show here that the binding of elastin peptides to their receptor activates the extracellular signal-regulated kinase (ERK) pathway; this activation is essential for the induction of pro-collagenase-1 production. Moreover, protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI(3)K) signaling were found to participate in ERK activation. Concomitantly, we demonstrate that stimulation by elastin peptides leads to enhanced DNA binding of activator protein-1 (AP-1). Our data indicate that the up-regulation of collagenase-1 following treatment of fibroblasts with elastin peptides results from a cross-talk between PKA, PI(3)K and the ERK signaling pathways and that this regulation is accompanied by activation of AP-1 transcription factors.

Adult↗

Involvement of secretory and cytosolic phospholipases A2 during infection of THP1 human monocytic cells with Toxoplasma gondii. Effect of interferon gamma.

Toxoplasma gondii is an intracellular, obligate protozoan parasite that actively invades host cells. Phospholipases A2 (PLA2) are widely distributed enzymes that exist in many isoforms [secretory (sPLA2), cytosolic (cPLA2)] in monocytic and other human cells (pancreatic, kidney, etc) and also in parasites. We examined the effects of inhibitors of sPLA2 type II and cPLA2 on the invasion of human monocytic cells (THP1) by T. gondii (RH strain). We also measured sPLA2 type II and cPLA2 enzyme activities and their modulation by interferon gamma (IFN gamma) in extracts of host cells and parasite. Inhibition of both parasite and THP1 sPLA2 type II, and of parasite cPLA2 reduced the number of infected cells. Enzyme assays and immunoblot analyses demonstrated T. gondii sPLA2 type II and cPLA2 activities and indicated that T. gondii increased the activity of THP1 sPLA2 type II. Incubation with IFN gamma (1,000 units/ml) for 20 h reduced the activities of sPLA2 and cPLA2 in infected and non-infected cells. Thus, IFN gamma blocks the activities of both THP1 and parasite sPLA2 and cPLA2 in membrane fractions, resulting in protection against active invasion by T. gondii.

Animals↗

Phosphatidylinositol 3-kinase regulates glycosylphosphatidylinositol hydrolysis through PLC-gamma(2) activation in erythropoietin-stimulated cells.

Erythropoietin (Epo)-induced glycosylphosphatidylinositol (GPI) hydrolysis was previously described to be correlated with phospholipase C-gamma 2 (PLC-gamma2) activation. Here, we analyzed the involvement of phosphatidylinositol (PtdIns) 3-kinase in GPI hydrolysis through PLC-gamma2 tyrosine phosphorylation in response to Epo in FDC-P1 cells transfected with a wild type (WT) erythropoietin-receptor (Epo-R). We showed that phosphatidylinositol 3-kinase (PtdIns 3-kinase) inhibitor LY294002 inhibits Epo-induced hydrolysis of endogenous GPI and Epo-induced PLC-gamma2 tyrosine phosphorylation in a dose-dependent manner. Wortmannin, another PtdIns 3-kinase inhibitor, also suppressed Epo-induced PLC-gamma2 tyrosine phosphorylation. We also present evidence that PLC-gamma2 translocation to the membrane fraction on Epo stimulation is completely inhibited by LY294002. Upon Epo stimulation, the tyrosine-phosphorylated PLC-gamma2 was found to be associated with the tyrosine-phosphorylated Grb2-associated binder (GAB)2, SHC and SHP2 proteins. LY294002 cell preincubation did not affect GAB2, SHC and SHP2 tyrosine phosphorylation but inhibited the binding of PLC-gamma2 to GAB2 and SHP2. Taken together, these results show that PtdIns 3-kinase controls Epo-induced GPI hydrolysis through PLC-gamma2.

Adaptor Proteins, Signal Transducing↗