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Lionel Larue

Publications and source records attributed to Lionel Larue.

At least 19 recordsLinked to original sources
PubMed2007

Notch1 and Notch2 receptors influence progressive hair graying in a dose-dependent manner.

The Notch signaling pathway is involved in diverse biological processes such as cell fate decisions or stem cell maintenance. In this study, we assessed the role of this pathway for melanocyte development and hair pigmentation using RBP-Jkappa, Notch1, and Notch2 conditional knockout mice. Disruption of the Notch pathway by inactivating RBP-Jkappa in the melanocyte lineage using Tyr::Cre mice led to a severe coat color dilution. Similarly, hair graying was observed when Notch1 and/or Notch2 receptors were ablated in melanocytes. This phenotype was proportional to the number of floxed Notch alleles, with the most pronounced effect seen in Tyr::Cre/degrees; Notch1(flox/flox); Notch2(flox/flox) mice. Deletion of Notch1 and/or Notch2 in melanoblasts did not induce a congenital defect. The number of Dct-expressing cells at embryonic stages was not affected, but melanocytes located within the hair matrix progressively disappeared during the first regeneration of the hair follicle. In contrast, non-follicular melanocytes and pigmentation in the dermis and in the choroid were not affected. We suggest that both Notch1 and Notch2 receptors contribute to the maintenance of melanoblasts and melanocyte stem cells, and are essential for proper hair pigmentation.

Alleles↗
PubMed2006

Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.

It is widely held that cells with metastatic properties such as invasiveness and expression of matrix metalloproteinases arise through the stepwise accumulation of genetic lesions arising from genetic instability and "clonal evolution." By contrast, we show here that in melanomas invasiveness can be regulated epigenetically by the microphthalmia-associated transcription factor, Mitf, via regulation of the DIAPH1 gene encoding the diaphanous-related formin Dia1 that promotes actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery. Low Mitf levels lead to down-regulation of Dia1, reorganization of the actin cytoskeleton, and increased ROCK-dependent invasiveness, whereas increased Mitf expression leads to decreased invasiveness. Significantly the regulation of Dia1 by Mitf also controls p27(Kip1)-degradation such that reduced Mitf levels lead to a p27(Kip1)-dependent G1 arrest. Thus Mitf, via regulation of Dia1, can both inhibit invasiveness and promote proliferation. The results imply variations in the repertoire of environmental cues that determine Mitf activity will dictate the differentiation, proliferative, and invasive/migratory potential of melanoma cells through a dynamic epigenetic mechanism.

Actins↗
PubMed2006

Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells.

Melanoblasts (Mbs) are thought to be strictly regulated by cell-cell interactions with epidermal keratinocytes, although the precise molecular mechanism of the regulation has been elusive. Notch signaling, whose activation is mediated by cell-cell interactions, is implicated in a broad range of developmental processes. We demonstrate the vital role of Notch signaling in the maintenance of Mbs, as well as melanocyte stem cells (MSCs). Conditional ablation of Notch signaling in the melanocyte lineage leads to a severe defect in hair pigmentation, followed by intensive hair graying. The defect is caused by a dramatic elimination of Mbs and MSCs. Furthermore, targeted overexpression of Hes1 is sufficient to protect Mbs from the elimination by apoptosis. Thus, these data provide evidence that Notch signaling, acting through Hes1, plays a crucial role in the survival of immature Mbs by preventing initiation of apoptosis.

Animals↗
PubMed2006

The WNT/Beta-catenin pathway in melanoma.

The Wnt/beta-catenin pathway is involved in various cellular activities--including determination, proliferation, migration and differentiation--in embryonic development and adult homeostasis. The deregulation or constitutive activation of the Wnt/beta-catenin pathway may lead to cancer formation. This review focuses on the role of the Wnt/beta-catenin canonical signaling pathway in the melanocyte lineage, and more specifically, in melanoma. Several components of the Wnt/beta-catenin pathway, such as APC, ICAT, LEF1 and beta-catenin are modified in melanoma tumors and cell lines, leading to activation of this signaling. A hallmark of the activation of this pathway is the presence of beta-catenin in the nucleus. Indeed, beta-catenin is found in about 30% of human melanoma nuclei, indicating a potentially specific role for this signaling pathway in this aggressive type of cancer. Beta-catenin can induce ubiquitous genes such as myc or cyclinD1, cell lineage-restricted genes such as Brn2 and melanocyte-specific genes such as Mitf-M and Dct. The Mitf-M and Brn-2 genes encode transcription factors. Mitf plays a critical role in melanocyte survival, proliferation and differentiation. Brn-2 is involved in melanoma proliferation. Determining how the Wnt/beta-catenin signaling pathway, alone or with other pathways, orchestrates the induction of target genes involved in a diverse range of activities represents a major challenge in research into melanoma formation and tumor progression.

Cell Adhesion Molecules↗
PubMed2006

Spatiotemporal gene control by the Cre-ERT2 system in melanocytes.

The organ-specific and temporal control of gene activation/inactivation is a key issue in the understanding of protein function during normal and pathological development and during oncogenesis. We generated transgenic mice bearing a tamoxifen-dependent Cre recombinase (Tyr::Cre-ERT2) gene expressed under the control of a 6.1 kb murine tyrosinase promoter in order to facilitate targeted spatiotemporally controlled somatic recombination in melanoblasts/melanocytes. Cre-ERT2 production was detected in tissues containing melanocytes. After tamoxifen induction at various times during embryogenesis and adulthood in a Cre-responsive reporter mouse strain, genetic recombination was detected in the melanoblasts and melanocytes of the skin. Thus, the Tyr::Cre-ERT2 transgenic mice provides a valuable tool for following this cell lineage and for investigating gene function in melanocyte development and transformation.

Animals↗
PubMed2006

[Hereditary diffuse gastric cancer].

Some diffuse type gastric cancers are of hereditary origin. Their histological characteristics are poor cell differentiation and the presence of signet-ring cells. The cause is a mutation of the CDH1 gene which is responsible for abnormal E-cadherin. The transmission mode is autosomal dominant. Because of serious prognosis of symptomatic hereditary diffuse gastric cancer (HDGC), the high penetrance of the gene (67% in men and 83% in women) and the young age of onset of these tumors (before the age of 40), a prophylactic gastrectomy is recommended to the mutation carriers. The search for the genetic mutation should be recommended to families corresponding to clinical criteria such as the number of affected family members, degree of relationship and age of onset of these tumors.

Adenocarcinoma↗
PubMed2005

Stable overexpression of Smad7 in human melanoma cells inhibits their tumorigenicity in vitro and in vivo.

We previously identified constitutive Smad signaling in human melanoma cells despite resistance to transforming growth factor-beta (TGF-beta) control of cell proliferation. This led us to investigate the effect of inhibitory Smad7 overexpression on melanoma cell behavior. Using the highly metastatic cell line, 1205-Lu, we thus generated melanoma cell clones constitutively expressing Smad7, and their mock-transfected counterparts. Stable expression of Smad7 resulted in an inhibition of constitutive Smad2/3 phosphorylation, and in a reduced TGF-beta response of Smad3/Smad4-driven gene transactivation, as measured using transfected Smad3/4-specific reporter gene constructs. Smad7 overexpression, however, did not alter their proliferative capacity and resistance to TGF-beta-driven growth inhibition. On the other hand, expression of Smad7 efficiently reduced the capacity of human melanoma cells to invade Matrigel in Boyden migration chambers, while not affecting their motility and adhesion to collagen and laminin. Gelatin zymography identified reduced MMP-2 and MMP-9 secretion by Smad7-expressing melanoma cells as compared with their control counterparts. Smad7-expressing melanoma cells exhibited a dramatically reduced capacity to form colonies under anchorage-independent culture conditions, and, when injected subcutaneously into nude mice, were largely delayed in their ability to form tumors. These results suggest that TGF-beta production by melanoma cells not only affects the tumor environment but also directly contributes to tumor cell aggressiveness through autocrine activation of Smad signaling.

Animals↗
PubMed2005

Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways.

Epithelial-mesenchymal transition (EMT) is an important process during development by which epithelial cells acquire mesenchymal, fibroblast-like properties and show reduced intercellular adhesion and increased motility. Accumulating evidence points to a critical role of EMT-like events during tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. Several oncogenic pathways (peptide growth factors, Src, Ras, Ets, integrin, Wnt/beta-catenin and Notch) induce EMT and a critical molecular event is the downregulation of the cell adhesion molecule E-cadherin. Recently, activation of the phosphatidylinositol 3' kinase (PI3K)/AKT axis is emerging as a central feature of EMT. In this review, we discuss the role of PI3K/AKT pathways in EMT during development and cancer with a focus on E-cadherin regulation. Interactions between PI3K/AKT and other EMT-inducing pathways are presented, along with a discussion of the therapeutic implications of modulating EMT in order to achieve cancer control.

Cadherins↗
PubMed2005

E-cadherin synergistically induces hepatospecific phenotype and maturation of embryonic stem cells in conjunction with hepatotrophic factors.

Since effective cell sourcing is a major challenge for the therapeutic management of liver disease and liver failure, embryonic stem (ES) cells are being widely investigated as a promising source of hepatic-like cells with their proliferative and pluripotent capacities. Cell-cell interactions are crucial in embryonic development modulating adhesive and signaling functions; specifically, the cell-cell adhesion ligand, cadherin is instrumental in gastrulation and hepatic morphogenesis. Inspired by the role of cadherins in development, we investigated the role of expression of E-cadherin in cultured murine ES cells on the induction of hepatospecific phenotype and maturation. The cadherin-expressing embryonic stem (CE-ES) cells intrinsically formed pronounced cell aggregates and cuboidal morphology whereas cadherin-deficient cadherin-expressing embryonic stem (CD-ES) cells remained more spread out and corded in morphology. Through controlled stimulation with single or combined forms of hepatotrophic growth factors; hepatocyte growth factor (HGF), dexamethasone (DEX) and oncostatin M (OSM), we investigated the progressive maturation of CE-ES cells, in relation to the control, CD-ES cells. Upon growth factor treatment, the CE-ES cells adopted a more compacted morphology, which exhibited a significant hepatocyte-like cuboidal appearance in the presence of DEX-OSM-HGF. In contrast, the CD-ES cells exhibited a mixed morphology and appeared to be more elongated in the presence of DEX-OSM-HGF. Reverse-transcriptase polymerase chain reaction was used to delineate the most differentiating condition in terms of early (alpha-fetoprotein (AFP)), mid (albumin), and late-hepatic (glucose-6-phosphatase) markers in relation to growth factor presentation for both CE-ES and CD-ES cells. We report that following the most differentiating condition of DEX-OSM-HGF stimulation, CE-ES cells expressed increased levels of albumin and glucose-6-phosphatase, whereas the CD-ES cells showed low levels of AFP and marginal levels of albumin and glucose-6-phosphatase. These trends suggest that the membrane expression of E-cadherin in ES cells can elicit a marked response to growth factor stimulation and lead to the induction of later stages of hepatocytic maturation. Thus, cadherin-engineered ES cells could be used to harness the cross-talk between the hepatotrophic and cadherin-based signaling pathways for controlled acceleration of ES hepatodifferentiation.

Animals↗
PubMed2005

Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression.

The controls that enable melanoblasts and melanoma cells to proliferate are likely to be related, but so far no key regulator of cell cycle progression specific to the melanocyte lineage has been identified. The microphthalmia-associated transcription factor Mitf has a crucial but poorly defined role in melanoblast and melanocyte survival and in differentiation. Here we show that Mitf can act as a novel anti-proliferative transcription factor able to induce a G1 cell-cycle arrest that is dependent on Mitf-mediated activation of the p21(Cip1) (CDKN1A) cyclin-dependent kinase inhibitor gene. Moreover, cooperation between Mitf and the retinoblastoma protein Rb1 potentiates the ability of Mitf to activate transcription. The results indicate that Mitf-mediated activation of p21Cip1 expression and consequent hypophosphorylation of Rb1 will contribute to cell cycle exit and activation of the differentiation programme. The mutation of genes associated with melanoma, such as INK4a or BRAF that would affect either Mitf cooperation with Rb1 or Mitf stability respectively, would impair Mitf-mediated cell cycle control.

Animals↗
PubMed2005

Ednrb2 orients cell migration towards the dorsolateral neural crest pathway and promotes melanocyte differentiation.

Endothelin receptors B (Ednrb) are involved in the development of the enteric and melanocytic lineages, which originate from neural crest cells (NCCs). In mice, trunk NCCs and their derivatives express only one Ednrb. In quail, trunk NCCs express two Ednrb: Ednrb and Ednrb2. Quail Ednrb is expressed in NCCs migrating along the ventral pathway, which gives rise to the peripheral nervous system, including enteric ganglia. Ednrb2 is upregulated in NCCs before these cells enter the dorsolateral pathway. The NCCs migrating along the dorsolateral pathway are melanocyte precursors. We analyzed the in vitro differentiation and in ovo migration of mouse embryonic stem (ES) cells expressing and not expressing Ednrb2. We generated a series of transfected ES cell lines expressing Ednrb2. This receptor, like Ednrb, oriented genuine ES cells towards melanocyte lineage differentiation in vitro. The in ovo migration of Ednrb2-expressing ES cells was massively oriented towards the dorsolateral pathway, unlike that of WT or Ednrb-expressing ES cells. Thus, Ednrb2 is involved in melanoblast differentiation and migration.

Animals↗
PubMed2004

Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells.

Expression of Snail transcriptional factor is a determinant in the acquisition of a mesenchymal phenotype by epithelial tumor cells. However, the regulation of the transcription of this gene is still unknown. We describe here the characterization of a human SNAIL promoter that contains the initiation of transcription and regulates the expression of this gene in tumor cells. This promoter was activated in cell lines in response to agents that induce Snail transcription and the mesenchymal phenotype, as addition of the phorbol ester PMA or overexpression of integrin-linked kinase (ILK) or oncogenes such as Ha-ras or v-Akt. Although other regions of the promoter were required for a complete stimulation by Akt or ILK, a minimal fragment (-78/+59) was sufficient to maintain the mesenchymal specificity. Activity of this minimal promoter and SNAIL RNA levels were dependent on ERK signaling pathway. NFkappaB/p65 also stimulated SNAIL transcription through a region located immediately upstream the minimal promoter, between -194 and -78. These results indicate that Snail transcription is driven by signaling pathways known to induce epithelial to mesenchymal transition, reinforcing the role of Snail in this process.

Cell Differentiation↗
PubMed2004

Involvement of cadherins 7 and 20 in mouse embryogenesis and melanocyte transformation.

We have determined the expression profiles of cdh7, and the related cdh20 during development. Both transcripts are found in the adult brain, but only cadherin-20 mRNA was detected during embryogenesis. In mouse embryos, cadherin-20 is synthesized by the forebrain, anterior neural ridge, developing visual system, primitive external granular layer of the cerebellum and a subset of neural crest cells likely to develop into melanoblasts. We found that the other embryonic tissues in which cadherin-20 was synthesized depended on genetic background. Melanoma cell lines contained transcripts for cadherin-7 but not for cadherin-20. The majority of the malignant melanoma cell lines produced N-cadherin (N-Cad) and/or cadherin-7 whereas melanocyte cell lines did not. The converse was observed for E-cadherin (E-Cad). Our data suggest that during development cadherin-20 is a key player in compartmentalization of the neural tube and establishment of neural circuitry. Finally, during oncogenesis, cadherin-7, N-cad and E-cad could be used as an efficient marker set for melanoma.

Amino Acid Sequence↗
PubMed2004

A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities.

More than a decade after their discovery, the three AKT kinase family members have emerged as central players in the signaling cascades that regulate cell growth, proliferation, survival and various aspects of intermediary metabolism. The mechanisms of activation of AKT kinases have been defined in relatively precise terms and new substrates are currently being validated in vivo. However, it is presently unclear whether AKT1, AKT2 and AKT3 are functionally redundant or whether each one performs specific functional role(s). In this review, we will summarize the signaling properties and highlight the specificities of AKT kinases that have emerged from the study of human cancer and animal models. While AKT kinases are an attractive target for pharmacological intervention, knowledge of the precise individual roles of AKT family members will improve the design of highly specific AKT-based therapeutics having reduced toxicity and improved efficacy.

Cell Enlargement↗
PubMed2004

Cell surface molecules and truncal neural crest ontogeny: a perspective.

The neural crest cell is synonymous with vertebrates and can be viewed as a transitory, mobile vector that conveys neuroepithelial stem cells to a diverse number of remote locations in the embryo. Neural crest cells have been studied intensively over the past 30 years, and it is increasingly apparent that their fate is, at least in part, directed extrinsically by the environment to which they are exposed in vivo. The interface between the cell surface and the opposing environment is clearly an important compartment for the correct deployment of the neural crest. Here, we review some of the molecules present in this location and how they influence the fate of the neural crest and generate disease.

Animals↗
PubMed2004

Dct::lacZ ES cells: a novel cellular model to study melanocyte determination and differentiation.

Embryonic stem (ES) cells differentiate into various cell lineages in vitro. A procedure was previously designed to promote the differentiation of ES cells towards the melanocyte lineage and to obtain large and reproducible amounts of melanocytes. To elucidate the main events that lead to the development of melanocytes in vitro, we used transgenic Dct::lacZ mouse blastocysts to establish ES cell lines expressing the lacZ reporter gene under the control of the Dct promoter. Dct, a melanoblast marker, is expressed just after melanoblast determination in vivo. We evaluated the importance of recruitment, proliferation and differentiation during melanocyte ontogeny after the in vitro differentiation of Dct::lacZ ES cells into melanocytes. We showed that bFGF and cholera toxin induce precocious melanoblast determination, associated with early melanocyte differentiation. Edn3 induced melanoblast proliferation and long-term melanoblast recruitment, but not precocious determination. The lack of basic Fibroblast Growth Factor (bFGF) and cholera toxin can be partially compensated by Edn3. Thus, Dct::lacZ ES cells can be used as a model to study determination, proliferation and differentiation in the melanocyte lineage in vitro.

Animals↗