| 1. |
- Andrae, Johanna, et al.
(författare)
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Platelet-derived growth factor-B and -C and active alpha-receptors in medulloblastoma cells.
- 2002
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Ingår i: Biochemical and biophysical research communications. - 0006-291X .- 1090-2104. ; 296:3, s. 604-11
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Tidskriftsartikel (refereegranskat)abstract
- The malignant childhood brain tumor medulloblastoma belongs to the group of primitive neuroectodermal tumours (PNETs). Medulloblastomas are thought to arise from remnants of the transient external germinal layer in the cerebellum. Proliferation, differentiation, and motility of cells in the central nervous system are regulated by growth factors, e.g., platelet-derived growth factor (PDGF). Recently, it was shown that higher level of PDGF alpha-receptor expression is characteristic of metastatic medulloblastomas. We have investigated five medulloblastoma/PNET cell lines and found that the PDGF alpha-receptor is actively signalling in most of them, an activity most likely driven by endogenously produced PDGF-C. PDGF-C is normally present in cells of the developing external germinal layer and our results are consistent with the idea that medulloblastomas are derived from such cells undergoing early neuronal differentiation. Moreover, the expression of PDGF and its receptors was associated with neuronal characteristics, but not with high levels of c-myc expression in the medullablastoma cells.
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| 2. |
- Arvidsson, Yvonne, 1960, et al.
(författare)
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ASK1 resistant neuroblastoma is deficient in activation of p38 kinase.
- 2001
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 8:10, s. 1029-37
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis Signal-regulating Kinase 1 (ASK1) is known to either induce apoptosis or differentiation in various cell lines of neuronal origin. We analyzed the effect of the constitutively active mutant of ASK1 (ASK1-Delta N) in an adenoviral vector in four neuroblastoma cell lines, two murine, C1300 and NXS2, and two human, SH-SY5Y and IMR-32. Already after 24 h upon infection, C1300 and SH-SY5Y cells arrested in growth when judged by [(3)H]thymidine incorporation, and the majority of the cells demonstrated apoptotic appearance, which was confirmed by DNA-laddering in gel electrophoresis. In contrast, NXS2 and IMR-32 cell lines remained unaffected. Immunoblotting revealed strongly phosphorylated p38 MAPK accompanied by weakly phosphorylated JNK in C1300 and SH-SY5Y, whereas none of these kinases were activated by adenoviruses expressing the kinase negative ASK1 mutant or beta-galactosidase. There was no expression of phosphorylated kinases in IMR-32 cells, but NXS2 showed a faint band of phosphorylated p38 MAPK. Addition of the p38 MAPK specific inhibitor, SB203580, protected C1300 and SH-SY5Y cells from apoptosis induced by ASK1-Delta N. The anti-neoplastic agent, paclitaxel, activates ASK1 and JNK, and promotes the in vitro assembly of stable microtubules. Addition of 10 nM paclitaxel sensitised the NXS2 cell line to ASK1-induced cell death. Our results indicate that ASK1 induces apoptosis in neuroblastoma cells mainly via the p38 MAPK pathway, and resistant neuroblastoma cells can be sensitised to ASK1 by paclitaxel.
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| 3. |
- Botchkarev, Vladimir A, et al.
(författare)
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Modulation of BMP signaling by noggin is required for induction of the secondary (nontylotrich) hair follicles.
- 2002
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Ingår i: The Journal of investigative dermatology. - : Elsevier BV. - 0022-202X. ; 118:1, s. 3-10
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Tidskriftsartikel (refereegranskat)abstract
- Increasing evidence suggests that morphogenesis of the distinct developmental structures derived from the same organ-committed epithelium is controlled by differential mechanisms. As was recently shown in mice with mutations in the downless (dL) gene, induction of primary or tylotrich hair follicles is strikingly dependent of signaling through the Tnf receptor homologue, Edar. Here, we show that dorsal skin of murine embryos with constitutive deletion of the BMP2/4 antagonist noggin, after transplantation into SCID mice, is characterized by the lack of induction of secondary hair follicles, and by the arrest of primary hair follicle development prior to hair shaft formation. The loss of noggin activity was associated with failure to express genes that specify hair follicle cell fates in the epidermis (Lef-1, beta-catenin, Shh) and dermal papilla (p75 kDa neurotrophin receptor, alkaline phosphatase). This suggests that regulation of BMP2/4 signaling by noggin is essential for the induction of secondary hair follicles, as well as for advanced stages of development in primary hair follicles.
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| 4. |
- Botchkarev, V A, et al.
(författare)
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Noggin is required for induction of the hair follicle growth phase in postnatal skin.
- 2001
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 15:12, s. 2205-14
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Tidskriftsartikel (refereegranskat)abstract
- During postnatal development, the hair follicle (HF) shows cyclic activity with periods of relative resting, active growth (anagen), and regression. We demonstrate that similar to the HF induction in embryonic skin, initiation of a new hair growth phase in postnatal skin requires neutralization of the inhibitory activity of bone morphogenetic protein 4 (BMP4) by the BMP antagonist noggin. In the resting HF, BMP4 mRNA predominates over noggin in the epithelium and mesenchyme, and the BMP receptor IA is prominently expressed in the follicular germ. Anagen development is accompanied by down-regulation of the BMP4 and increased noggin mRNA in the HF. Furthermore, administration of noggin protein induces new hair growth phase in postnatal telogen skin in vivo. In contrast, BMP4 induces selective arrest of anagen development in the non-tylotrich (secondary) HF. As a hair growth inducer, noggin increases Shh mRNA in the HF whereas BMP4 down-regulates Shh. This suggests that modulation of BMP4 signaling by noggin is essential for hair growth phase induction in postnatal skin and that the hair growth-inducing effect of noggin is mediated, at least in part, by Shh.
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| 5. |
- Brederlau, Anke, 1968, et al.
(författare)
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Bone morphogenetic proteins but not growth differentiation factors induce dopaminergic differentiation in mesencephalic precursors.
- 2002
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Ingår i: Molecular and cellular neurosciences. - 1044-7431. ; 21:3, s. 367-78
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs) are potential therapeutic molecules for the treatment of Parkinson's disease (PO). Here we compare the effects of BMP3, 5, 6, and 7 and GDF5 and 6 in a rat mesencephalic cell culture system that reflects the developmental stage of neurons around birth. High concentrations of BMP5, 6, and 7 and GDF5 and 6 induced astroglial cell fate and a depletion of oligodendrocytes. Only BMP5, 6, and 7, however, significantly increased the number of tyrosine hydroxylase (TH)-positive neurons and induced nuclear translocation of the phosphorylated BMP-restricted Smad in a substantial number of TH- and microtubule-associated protein 2(MAP2ab)-positive cells. None of the proteins protected TH-positive cells against 6-hydroxydopamine-induced oxidative stress. BMP3 was without any effect throughout the studies. We conclude that BMP5, 6, and 7 act directly and independently on precursors of the dopaminergic and astroglial lineage and induce their differentiation. In contrast, GDF5 and 6 primarily affect nonneuronal cells in mesencephalic cultures of this stage.
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| 6. |
- Brederlau, Anke, 1968, et al.
(författare)
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The bone morphogenetic protein type Ib receptor is a major mediator of glial differentiation and cell survival in adult hippocampal progenitor cell culture.
- 2004
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Ingår i: Molecular biology of the cell. - 1059-1524. ; 15:8, s. 3863-75
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic proteins (BMPs) act as growth regulators and inducers of differentiation. They transduce their signal via three different type I receptors, termed activin receptor-like kinase 2 (Alk2), Alk3, or bone morphogenetic protein receptor Ia (BMPRIa) and Alk6 or BMPRIb. Little is known about functional differences between the three type I receptors. Here, we have investigated consequences of constitutively active (ca) and dominant negative (dn) type I receptor overexpression in adult-derived hippocampal progenitor cells (AHPs). The dn receptors have a nonfunctional intracellular but functional extracellular domain. They thus trap BMPs that are endogenously produced by AHPs. We found that effects obtained by overexpression of dnAlk2 and dnAlk6 were similar, suggesting similar ligand binding patterns for these receptors. Thus, cell survival was decreased, glial fibrillary acidic protein (GFAP) expression was reduced, whereas the number of oligodendrocytes increased. No effect on neuronal differentiation was seen. Whereas the expression of Alk2 and Alk3 mRNA remained unchanged, the Alk6 mRNA was induced after impaired BMP signaling. After dnAlk3 overexpression, cell survival and astroglial differentiation increased in parallel to augmented Alk6 receptor signaling. We conclude that endogenous BMPs mediate cell survival, astroglial differentiation and the suppression of oligodendrocytic cell fate mainly via the Alk6 receptor in AHP culture.
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| 7. |
- Egawa-Tsuzuki, Tomoko, et al.
(författare)
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The PDGF B-chain is involved in the ontogenic susceptibility of the developing rat brain to NMDA toxicity.
- 2004
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Ingår i: Experimental neurology. - : Elsevier BV. - 0014-4886. ; 186:1, s. 89-98
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxic-ischemic (H-I) injury to neonatal brains can cause a life-long neuronal deficit because of increased susceptibility in the neonatal period. Excitotoxicity due to overstimulation of the N-methyl-d-aspartate receptor (NMDAR) is assumed to be the basis of the injury. However, the ontogenic profile of the susceptibility does not directly correlate with the levels of NMDAR expression. Platelet-derived growth factor B-chain (PDGF-B) has been reported to protect neurons by suppressing the NMDA-evoked current and translocating the glutamate transporter to the cell membrane. Thus, we assessed the relationship between the susceptibility to H-I injury and the expression of PDGF-B in neonatal rat brain. PDGF-B infusion before and after an intrastriatal NMDA injection significantly reduced the size of the lesions in 7-day-old rats, when they are most susceptible and the neuronal expression of PDGF-B is low. Fourteen-day-old neonatal rats were found to be resistant to NMDA injury, even though NMDARs are expressed at high levels in the brain at this age. Inhibition of PDGF-B protein synthesis by antisense oligodeoxynucleotides increased the size of the NMDA-induced lesions up to 6-fold at postnatal day 14, when PDGF-B is expressed at high levels in neurons. These data suggest that PDGF-B is an important physiological modulator of NMDAR excitability in the developing brain, and that the balance between the expression of NMDAR and PDGF-B partly determines the ontogenic susceptibility to brain injury. Enhancement of the PDGF-B/receptor signal pathway might rescue neonatal brains at risk of H-I injury.
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| 8. |
- Faigle, Roland, 1977, et al.
(författare)
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ASK1 inhibits astroglial development via p38 mitogen-activated protein kinase and promotes neuronal differentiation in adult hippocampus-derived progenitor cells.
- 2004
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Ingår i: Molecular and cellular biology. - 0270-7306. ; 24:1, s. 280-93
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms controlling differentiation and lineage specification of neural stem cells are still poorly understood, and many of the molecules involved in this process and their specific functions are yet unknown. We investigated the effect of apoptosis signal-regulating kinase 1 (ASK1) on neural stem cells by infecting adult hippocampus-derived rat progenitors with an adenovirus encoding the constitutively active form of ASK1. Following ASK1 overexpression, a significantly larger number of cells differentiated into neurons and a substantial increase in Mash1 transcription was observed. Moreover, a marked depletion of glial cells was observed, persisting even after additional treatment of ASK1-infected cultures with potent glia inducers such as leukemia inhibitory factor and bone morphogenetic protein. Analysis of the promoter for glial fibrillary acidic protein revealed that ASK1 acts as a potent inhibitor of glial-specific gene transcription. However, the signal transducers and activators of transcription 3 (STAT3)-binding site in the promoter was dispensable, while the activation of p38 mitogen-activated protein kinase was crucial for this effect, suggesting the presence of a novel mechanism for the inhibition of glial differentiation.
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| 9. |
- Funa, Keiko, 1949, et al.
(författare)
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Regulatory mechanisms for the expression and activity of platelet-derived growth factor receptor.
- 2003
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Ingår i: Acta biochimica Polonica. - 0001-527X. ; 50:3, s. 647-58
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Forskningsöversikt (refereegranskat)abstract
- PDGF is one of the most potent serum mitogens, and the signalling mechanism by way of its receptor tyrosine-kinase has been extensively studied since its first purification in 1979. The identification of homology between the simian sarcoma virus oncogene, v-sis, and the B-chain of PDGF, as well as the frequent over-expression of both the ligands and receptors in various tumours and stroma led to the proposal of the PDGF-mediated autocrine and paracrine hypothesis. Consistent with the important roles of PDGF in the growth and survival of cells, the expression and activity of PDGF receptors are tightly controlled by both positive and negative feedback mechanisms at different levels. The deregulation of the control system can result in serious pathological conditions such as chronic inflammation and tumours. Understanding the molecular mechanisms for the regulatory system and the signalling pathway of PDGF is essential in order to find effective therapies in the diseases where PDGF is involved.
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| 10. |
- Hackzell, Anders, 1973, et al.
(författare)
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p73 independent of c-Myc represses transcription of platelet-derived growth factor beta-receptor through interaction with NF-Y.
- 2002
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Ingår i: The Journal of biological chemistry. - 0021-9258. ; 277:42, s. 39769-76
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Tidskriftsartikel (refereegranskat)abstract
- We recently reported that c-Myc represses the transcription of platelet-derived growth factor (PDGF) beta-receptor (Izumi, H., Molander, C., Penn, L. Z., Ishisaki, A., Kohno, K., and Funa, K. (2001) J. Cell Sci. 114, 1533-1544). We demonstrate here that the p53 family protein p73alpha represses PDGF beta-receptor transcription essentially by the same mechanism. p73alpha but not p73beta or p53 represses the transcription in concordance with its ability to bind NF-YC and NF-YB. None of other p73 isoforms (i.e. p73beta, p73gamma, p73epsilon), C-terminal deletion mutants of p73alpha, and p53 is able to bind NF-Y with the exception of p63alpha. This finding suggests that the sterile alpha-motif domain present only in p73alpha and p63alpha is the interaction site. For the repression, the N-terminal transactivation domain of p73alpha is also indispensable, arguing for the importance of the activity of p73alpha in the mechanism. p73alpha binds the C-terminal HAP domain of NF-YC previously found to be the interaction site with c-Myc and TBP. Because c-Myc induces and activates p73alpha (Zaika, A., Irwin, M., Sansome, C., and Moll, U. M. (2001) J. Biol. Chem. 276, 11310-11316) and they bind each other (Uramoto, H., Izumi, H., Ise, T., Tada, M., Uchiumi, T., Kuwano, M., Yasumoto, K., Funa, K., and Kohno, K. (2002) J. Biol. Chem. 277, in press), we examined whether the repression by p73 is dependent on c-Myc. However, Myc-null rat fibroblasts are also susceptible to p73alpha-induced repression. Serum stimulation of NIH3T3 cells gradually decreased the amount of endogenous NF-Y binding to the PDGF beta-receptor promoter, whereas NF-YA expression in the nuclear extracts remains unchanged. Our results indicate that serum stimulation induces c-Myc and p73alpha, leading to the down-regulation of PDGF beta-receptor expression by repressing its transcription.
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