Biomedical subjects

Laurent Debelle

Publications and source records attributed to Laurent Debelle.

4 recordsLinked to original sources

PubMed2005

Elastin peptides activate extracellular signal-regulated kinase 1/2 via a Ras-independent mechanism requiring both p110gamma/Raf-1 and protein kinase A/B-Raf signaling in human skin fibroblasts.

Elastin peptides (EPs) produced during cancer progression bind to the elastin binding protein (EBP) found at the surface of dermal fibroblasts, leading to the expression of collagenase-1 gene. The production of this enzyme involved in stromal reaction is caused by the sustained activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway via cAMP/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K). However, the mechanism of these signaling events remains unknown. We show that kappa-elastin (kappaE), a commonly used EP, induces maximum phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)1/2 and ERK1/2 after 30 min. The simultaneous inhibition of PKA and PI3K, by N-(2-(p-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide (H89) and 2-(4-morpholynil)-8-phenyl-4H-1-bemzopyran-4-one (LY294002), respectively, blocked MEK1/2 and ERK1/2 phosphorylation, as did lactose, an EBP antagonist. kappaE induced Raf-1 phosphorylation and activation in a PI3K-dependent manner. In our system, the PI3K p110gamma is expressed and activated by betagamma-derived subunits from a pertussis toxin-sensitive G protein after fibroblast stimulation. Pertussis toxin also blocks the Raf-1/MEK1/2/ERK1/2 phosphorylation cascade. In addition, we found that B-Raf is expressed in dermal fibroblasts and activated in a PKA-dependent manner after kappaE treatment, thereby integrating PKA signals to MEK1/2. It is noteworthy that Ras involvement was excluded because ERK1/2 activation by kappaE was not blocked in RasN17-transfected fibroblasts. Together, our results identify a novel Ras-independent ERK1/2 activation system in which p110gamma/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. Thus, p110gamma and B-Raf seem to be important modulators of dermal fibroblasts physiology and should now qualify as therapeutic targets in strategies aiming at limiting elastin degradation contribution to cancer progression.

Cells, Cultured↗

PubMed2004

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↗

PubMed2002

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↗

PubMed2002

Cumulative influence of elastin peptides and plasminogen on matrix metalloproteinase activation and type I collagen invasion by HT-1080 fibrosarcoma cells.

HT-1080 fibrosarcoma cells express at their plasma membrane the elastin-binding protein (EBP). Occupancy of EBP by elastin fragments, tropoelastin or XGVAPG peptides was found to trigger procollagenase-1 (proMMP-1) overproduction by HT-1080 cells at the protein and enzyme levels. RT-PCR analysis indicated that elastin peptides did not modify the MMP-1 mRNA steady state levels, suggesting the involvement of a post-transcriptional mechanism. We previously reported that binding of elastin peptides to EBP induced other matrix metalloproteinases (MMP-2 and MT1-MMP) expression. Since those peptides were here found to also accelerate the secretion of urokinase from HT-1080 cells, culture medium was supplemented with plasminogen together with elastin peptides at aims to induce or potentiate MMPs activation cascades. In such conditions, plasmin activity was generated and exacerbate proMMP-1 and proMMP-2 activation. As a consequence, elastin peptides and plasminogen-treated HT-1080 cells displayed a significant type I collagen matrix invasive capacity.

Collagen Type I↗