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P Mehlen

Publications and source records attributed to P Mehlen.

At least 19 recordsLinked to original sources
PubMed2005

Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers.

Although cancer is a multifaceted disease, all cancer types share identical molecular and cellular mechanisms. These mechanisms involve a collection of alterations critical to the normal physiological functioning of cells, such as alterations of growth factor signalling pathways, angiogenesis, cell adhesion signals, DNA replication and apoptotic cell death. Many genes involved in the processes enumerated above are functionally inactive in tumour cells, designating them as putative 'tumour suppressor genes'. Back in the early 1990s, Vogelstein and colleagues suggested that a gene called DCC (for Deleted in Colorectal Cancer) could be a tumour suppressor gene because it was found to be deleted in more than 70% of colorectal cancers, as well as in many other cancers. During the last 15 years, controversial data have failed to firmly establish whether DCC is indeed a tumour suppressor gene. However, the recent observations that DCC triggers cell death and is a receptor for netrin-1, a molecule recently implicated in colorectal tumorigenesis, have prompted a renewal of interest in the role of DCC in tumorigenesis and suggest that the netrin-1/receptor pairs act as novel negative regulators of tumour development.

Colorectal Neoplasms↗
PubMed2005

Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis.

Netrin-1 has been shown to play a crucial role in neuronal navigation during nervous system development mainly through its interaction with its receptors DCC and UNC5H. However, initially the DCC (deleted in colorectal cancer) gene was proposed as a putative tumor suppressor gene. It was then difficult to reconcile the two activities of DCC until the observation that DCC belongs to an emerging family of receptors named dependence receptors. Such receptors share the property of inducing apoptosis in the absence of ligand, hence creating a cellular state of dependence on the ligand. Thus, netrin-1 may not only be a chemotropic factor for neurons but also a survival factor. We will review here the identification of netrin-1 and its receptors, the signaling pathways initiated in the presence or absence of netrin-1. We will suggest some possible roles of netrin-1 in nervous system development, neovascularisation, adhesion and tumorigenesis.

Animals↗
PubMed2005

[Netrin-1 and its dependence receptors: role in colorectal cancers].

Currently, an increasing number of receptors appear to belong to the dependence receptors family. These proteins have the capacity to induce a program of apoptosis in settings of absence of their ligand. A cell that expresses one of these receptors is thus dependent on the presence of the ligand to survive. The observation that these receptors are lost in many cancers is then suggesting that this loss is a selective advantage for tumor development because it leads tumor cells not to be dependent for survival on the presence of the ligand. We propose to focus this review on the role of some of these receptors that have been intensively studied: the dependence receptors that bind the netrin-1. After having pointed out their role in the development of the nervous system and in cell death induction, we will discuss their putative role in the pathological context of tumorigenesis and more particularly in the control of colorectal cancers.

Animals↗
PubMed2005

Receptors that mediate cellular dependence.

Cells depend for their survival on stimulation by trophic factors and other prosurvival signals, the withdrawal of which induces apoptosis, both via the loss of antiapoptotic signaling and the activation of proapoptotic signaling via specific receptors. These receptors, dubbed dependence receptors, activate apoptotic pathways following the withdrawal of trophic factors and other supportive stimuli. Such receptors may feature in developmental cell death, carcinogenesis (including metastasis), neurodegeneration, and possibly subapoptotic events such as neurite retraction and somal atrophy. Mechanistic studies of dependence receptors suggest that these receptors form ligand-dependent complexes that include specific caspases. Complex formation in the absence of ligand leads to caspase activation by a mechanism that is typically dependent on caspase cleavage of the receptor itself, releasing proapoptotic peptides. Cellular dependence receptors, considered in the aggregate, may thus form a system of molecular integration, analogous to the electrical integration system provided by dendritic arbors in the nervous system.

Animals↗
PubMed2004

Dependence receptors: between life and death.

The recently described family of dependence receptors is a new family of functionally related receptors. These proteins have little sequence similarity but display the common feature of inducing two completely opposite intracellular signals depending on ligand availability: in the presence of ligand, these receptors transduce a positive signal leading to survival, differentiation or migration, while in the absence of ligand, the receptors initiate or amplify a negative signal for apoptosis. Thus, cells that express these proteins manifest a state of dependence on their respective ligands. The mechanisms that trigger cell death induction in the absence of ligand are in large part unknown, but typically require cleavage by specific caspases. In this review we will present the proposed mechanisms for cell death induction by these receptors and their potential function in nervous system development and regulation of tumorigenesis.

Animals↗
PubMed2004

The dependence receptor hypothesis.

A new family of functionally-related receptors has recently been proposed, dubbed dependence receptors. These proteins, only some of which share sequence similarities, display the common property that they transduce two different intracellular signals: in the presence of ligand, these receptors transduce a positive signal leading to survival, differentiation or migration; conversely, in the absence of ligand, the receptors initiate or amplify a signal for programmed cell death. Thus cells that express these proteins at sufficient concentrations manifest a state of dependence on their respective ligands. The signaling that mediates cell death induction upon ligand withdrawal is in large part uncharacterized, but typically includes a required interaction with, and cleavage by, specific caspases. Here, we review the current knowledge concerning dependence receptors, including the shared mechanisms for cell death induction and their potential relevance in nervous system development and regulation of tumorigenesis.

Animals↗
PubMed2002

Expression of netrin-1 and netrin-1 receptor, DCC, in the rat olfactory nerve pathway during development and axonal regeneration.

Netrin-1 is a bifunctional secreted protein that directs axon extension in various groups of developing axonal tracts. The transmembrane DCC (deleted in colorectal cancer) receptor is described as netrin-1 receptor and is involved in the attractive effects of netrin-1. In this study, we examined the spatio-temporal expression patterns of both netrin-1 and DCC in the rat olfactory system at different stages of development and during axonal regeneration following unilateral bulbectomy. High DCC expression was detected on the pioneer olfactory axons as they are extending toward the telencephalon. This expression was transient since from embryonic day 16 onwards, DCC was no longer detected along the olfactory nerve path. From embryonic day 14 until birth, DCC was also expressed within the mesenchyme surrounding the olfactory epithelium. During the same period, netrin-1 protein was detected along the trajectory of olfactory axons up to the olfactory bulb and its expression pattern in the nasal mesenchyme largely overlapped that of DCC. Moreover, netrin-1 continued to be present during the two first post-natal weeks, and a weak protein expression still persisted in the dorso-medial region of the olfactory epithelium in adult rats. While unilateral bulbectomy induced a transient up-regulation of netrin-1 in the lamina propria, particularly in the dorso-medial region of the neuroepithelium, no DCC expression was detected on the regenerating olfactory axons. In the developing olfactory bulb, the extension of mitral cell axons was associated with DCC presence while netrin-1 was absent along this axonal path. DCC was also highly expressed in the newly formed glomeruli after birth, and a weak DCC expression was still detected in the glomerular layer in adult rats. Taken together, these data support the notion that netrin-1, via DCC expressed on axons, may play a role in promoting outgrowth and/or guidance of pioneering olfactory axons toward the olfactory bulb primordium. Moreover, association of netrin-1 with mesenchymal DCC may provide a permissive environment to the growth of both pioneer and later-growing axons. The maintenance of netrin-1 expression in the nasal mesenchyme of adult rats as well as its regional up-regulation following unilateral bulbectomy infer that netrin-1, even in the absence of DCC, may be involved in the process of axonal growth of newly differentiated olfactory receptor neurons probably through the use of other receptors.

Animals↗
PubMed2002

Serine protease inhibitor Spi2 mediated apoptosis of olfactory neurons.

The olfactory epithelium of adult mouse, where primary sensory neurons are massively committed to apoptosis by removal of their synaptic target, was used as a model to determine in vivo mechanisms for neuronal cell death induction. A macro-array assay revealed that the death of olfactory neurons is accompanied with over-expression of the serine protease inhibitor Spi2. This over-expression is associated with decreased serine protease activity in the olfactory mucosa. Moreover, in vitro or in vivo inhibition of serine proteases induced apoptotic death of olfactory neuronal cells. Interestingly, Spi2 over-expression is not occurring in olfactory neurons but in cells of the lamina propria, suggesting that Spi2 may act extracellularly as a cell death inducer. In that sense, we present evidence that in vitro Spi2 overexpression generates a secreted signal for olfactory neuron death. Hence, taken together these results document a possible novel mechanism for apoptosis induction that might occur in response to neurodegenerative insults.

Animals↗
PubMed2001

Netrin-1 acts as a survival factor via its receptors UNC5H and DCC.

The membrane receptors DCC and UNC5H have been shown to be crucial for axon guidance and neuronal migration by acting as receptors for netrin-1. DCC has also been proposed as a dependence receptor inducing apoptosis in cells that are beyond netrin-1 availability. Here we show that the netrin-1 receptors UNC5H (UNC5H1, UNC5H2, UNC5H3) also act as dependence receptors. UNC5H receptors induce apoptosis, but this effect is blocked in the presence of netrin-1. Moreover, we demonstrate that UNC5H receptors are cleaved in vitro by caspase in their intracellular domains. This cleavage may lead to the exposure of a fragment encompassing a death domain required for cell death induction in vivo. Finally, we present evidence that during development of the nervous system, the presence of netrin-1 is crucial to maintain survival of UNC5H- and DCC-expressing neurons, especially in the ventricular zone of the brainstem. Altogether, these results argue for a role of netrin-1 during the development of the nervous system, not only as a guidance cue but as a survival factor via its receptors DCC and UNC5H.

Animals↗
PubMed2001

The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation.

The expression of DCC (deleted in colorectal cancer) is often markedly reduced in colorectal and other cancers. However, the rarity of point mutations identified in DCC coding sequences and the lack of a tumor predisposition phenotype in DCC hemizygous mice have raised questions about its role as a tumor suppressor. DCC also mediates axon guidance and functions as a dependence receptor; such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand. We now show that DCC drives cell death independently of both the mitochondria-dependent pathway and the death receptor/caspase-8 pathway. Moreover, we demonstrate that DCC interacts with both caspase-3 and caspase-9 and drives the activation of caspase-3 through caspase-9 without a requirement for cytochrome c or Apaf-1. Hence, DCC defines an additional pathway for the apoptosome-independent caspase activation.

Apoptosis↗
PubMed2000

Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor.

The netrins, a family of laminin-related secreted proteins, are critical in controlling axon elongation and pathfinding. The DCC (for deleted in colorectal cancer) protein was proposed as a receptor for netrin-1 in the light of many observations including the inhibition of netrin-1-mediated axon outgrowth and attraction in the presence of an anti-DCC antiserum, the similitude of nervous system defects in DCC and netrin-1 knockout mice and the results of receptor swapping experiments. Previous studies have failed to show a direct interaction of DCC with netrin-1 (ref. 10), suggesting the possibility of an additional receptor or co-receptor. Here we show that DCC interacts with the membrane-associated adenosine A2b receptor, a G-protein-coupled receptor that induces cAMP accumulation on binding adenosine. We show that A2b is actually a netrin-1 receptor and induces cAMP accumulation on binding netrin-1. Finally, we show that netrin-1-dependent outgrowth of dorsal spinal cord axons directly involves A2b. Together our results indicate that the growth-promoting function of netrin-1 may require a receptor complex containing DCC and A2b.

Animals↗
PubMed2000

The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.

The RET (rearranged during transfection) proto-oncogene encodes a tyrosine kinase receptor involved in both multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome, and Hirschsprung disease (HSCR), a developmental defect of enteric neurons. We report here that the expression of RET receptor induces apoptosis. This pro-apoptotic effect of RET is inhibited in the presence of its ligand glial cell line-derived neurotrophic factor (GDNF). Furthermore, we present evidence that RET induces apoptosis via its own cleavage by caspases, a phenomenon allowing the liberation/exposure of a pro-apoptotic domain of RET. In addition, we report that Hirschsprung-associated RET mutations impair GDNF control of RET pro-apoptotic activity. These results indicate that HSCR may result from apoptosis of RET-expressing enteric neuroblasts.

Apoptosis↗
PubMed2000

[Dependence receptors: links between apoptosis, nervous system development and control of tumorigenesis].

The dependence receptor notion was based on the observation that the effects of a number of receptors that function in both nervous system development and tumorigenesis (especially metastasis) cannot be explained simply by a positive effect of signal transduction induced by ligand binding. Receptors such as the common neurotrophin receptor p75NTR, the androgen receptor (AR), DCC (deleted in colorectal cancer), and RET (rearranged during transfection) demonstrate effects that are more adequately explained when these are considered to be dependence receptors. These receptors show two distinct forms of signal transduction depending on their respective ligand availability: in the presence of their ligands, they transduce a signal for either proliferation or differentiation; however, they are not inactive in the absence of their ligands, but rather induce an active signal for cell death. Such receptors thus create a cellular state of dependence on their ligands, the loss of ligand availability inducing cell suicide or enhancing the likelihood of cellular suicide. This new concept is reviewed here enlightening the molecular mechanisms of these receptors and their potential relevance in vivo in the development of the nervous system and in the control of tumorigenesis.

Animals↗
PubMed1999

TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction.

The common neurotrophin receptor, p75(NTR), has been shown to signal in the absence of Trk tyrosine kinase receptors, including induction of neural apoptosis and activation of NF-kappaB. However, the mechanisms by which p75(NTR) initiates these intracellular signal transduction pathways are unknown. Here we report interactions between p75(NTR) and the six members of TRAF (tumor necrosis factor receptor-associated factors) family proteins. The binding of different TRAF proteins to p75(NTR) was mapped to distinct regions in p75(NTR). Furthermore, TRAF4 interacted with dimeric p75(NTR), whereas TRAF2 interacted preferentially with monomeric p75(NTR). TRAF2-p75(NTR), TRAF4-p75(NTR), and TRAF6-p75(NTR) interactions modulated p75(NTR)-induced cell death and NF-kappaB activation with contrasting effects. Coexpression of TRAF2 with p75(NTR) enhanced cell death, whereas coexpression of TRAF6 was cytoprotective. Furthermore, overexpression of TRAF4 abrogated the ability of dimerization to prevent the induction of apoptosis normally mediated by monomeric p75(NTR). TRAF4 also inhibited the NF-kappaB response, whereas TRAF2 and TRAF6 enhanced p75(NTR)-induced NF-kappaB activation. These results demonstrate that TRAF family proteins interact with p75(NTR) and differentially modulate its NF-kappaB activation and cell death induction.

Apoptosis↗
PubMed1999

Small stress protein Hsp27 accumulation during dopamine-mediated differentiation of rat olfactory neurons counteracts apoptosis.

The small stress protein Hsp27 is expressed during mammalian neural development. We have analyzed the role of this protein in immortalized rat olfactory neuroblasts. In the presence of dopamine a fraction of these cells differentiate into neurons while the remaining cells undergo apoptosis. We report here that the dopamine induced differentiation and apoptosis are associated with a transient and specific accumulation of Hsp27. Moreover, transfection experiments have shown that Hsp27 overexpression drastically decreases the fraction of cells undergoing apoptosis. In contrast, reduction of the endogenous level of Hsp27 led to abortion of differentiation and, therefore, drastically increased the number of apoptotic cells. Furthermore, in the normal cell population we show that Hsp27 accumulation takes place only in differentiating cells that were not undergoing apoptosis. We therefore conclude that Hsp27 may represent a key protein that controls the decision of olfactory precursor cells to undergo either differentiation or cell death.

Animals↗
PubMed1998

Heat shock protein 27 enhances the tumorigenicity of immunogenic rat colon carcinoma cell clones.

The REG and PRO cell clones were obtained from a colon adenocarcinoma induced in a BDIX rat by 1,2-dimethylhydrazine. When injected s.c. into syngeneic hosts, REG cells induce tumors that regress in less than 3 weeks, whereas PRO cells, like parental cells, induce progressive tumors. Here, we show that compared to PRO cells, REG cells are more sensitive to cell death induced by anticancer drugs. The small heat shock protein (HSP) 27 is not expressed or inducible in REG clones, whereas it is abundantly expressed and inducible by heat shock in PRO clones. The expression of HSP27 in REG cells increases their resistance to apoptosis in vitro and dramatically enhances their tumorigenicity when injected s.c. into syngeneic rats. HSP27 expression in REG cells both increases tumor size and delays tumor regression. This increased tumorigenicity is associated with a substantial decrease of in vivo tumor cell apoptosis. We conclude that HSP27 expression in malignant cells increases their tumorigenicity in syngeneic animals. In combination with the role of HSP27 in tumor cell resistance to cytotoxic agents, its contribution to tumorigenicity makes this protein a potential target for antitumoral therapy.

Adenocarcinoma↗