Increased progenitor proliferation and apoptotic cell death in the sensory lineage of mice overexpressing N-myc

Kobayashi, Miwako; Hjerling-Leffler, Jens; Ernfors, Patrik

doi:10.1007/s00441-005-0011-5

Cited by 5 publications

(5 citation statements)

References 40 publications

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“…CaBPs have in mouse mainly been studied as markers for the diverse neuron populations, especially during development and in cultures (e.g. [19,20,28,[30][31][32]), but detailed in vivo quantitative and colocalization analyses of adult mDRGs are less common. Nevertheless, Ichikawa et al [50] reported the presence of PV-LI in~5% of adult mDRG NPs.…”

Section: Other Cabps In Drgsmentioning

confidence: 99%

“…In addition, the spinal dorsal horn and spinal trigeminal nucleus, regions important for sensory information processing, including pain, have been studied. They include chicken [21][22][23], Xenopus laevis [24], turtle [25], zebra fish [26], dog [27], mouse [28][29][30][31][32] and, most thoroughly, rat [2,21,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. However, caveats of knowledge exist regarding the cellular sites of Scgn mRNA expression and protein distribution in DRGs or spinal cord.…”

Section: Introductionmentioning

confidence: 99%

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Secretagogin is Expressed in Sensory CGRP Neurons and in Spinal Cord of Mouse and Complements other Calcium-Binding Proteins, with a Note on Rat and Human

et al. 2012

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BackgroundSecretagogin (Scgn), a member of the EF-hand calcium-binding protein (CaBP) superfamily, has recently been found in subsets of developing and adult neurons. Here, we have analyzed the expression of Scgn in dorsal root ganglia (DRGs) and trigeminal ganglia (TGs), and in spinal cord of mouse at the mRNA and protein levels, and in comparison to the well-known CaBPs, calbindin D-28k, parvalbumin and calretinin. Rat DRGs, TGs and spinal cord, as well as human DRGs and spinal cord were used to reveal phylogenetic variations.ResultsWe found Scgn mRNA expressed in mouse and human DRGs and in mouse ventral spinal cord. Our immunohistochemical data showed a complementary distribution of Scgn and the three CaBPs in mouse DRG neurons and spinal cord. Scgn was expressed in ~7% of all mouse DRG neuron profiles, mainly small ones and almost exclusively co-localized with calcitonin gene-related peptide (CGRP). This co-localization was also seen in human, but not in rat DRGs. Scgn could be detected in the mouse sciatic nerve and accumulated proximal to its constriction. In mouse spinal cord, Scgn-positive neuronal cell bodies and fibers were found in gray matter, especially in the dorsal horn, with particularly high concentrations of fibers in the superficial laminae, as well as in cell bodies in inner lamina II and in some other laminae. A dense Scgn-positive fiber network and some small cell bodies were also found in the superficial dorsal horn of humans. In the ventral horn, a small number of neurons were Scgn-positive in mouse but not rat, confirming mRNA distribution. Both in mouse and rat, a subset of TG neurons contained Scgn. Dorsal rhizotomy strongly reduced Scgn fiber staining in the dorsal horn. Peripheral axotomy did not clearly affect Scgn expression in DRGs, dorsal horn or ventral horn neurons in mouse.ConclusionsScgn is a CaBP expressed in a subpopulation of nociceptive DRG neurons and their processes in the dorsal horn of mouse, human and rat, the former two co-expressing CGRP, as well as in dorsal horn neurons in all three species. Functional implications of these findings include the cellular refinement of sensory information, in particular during the processing of pain.

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Section: Other Cabps In Drgsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Secretagogin is Expressed in Sensory CGRP Neurons and in Spinal Cord of Mouse and Complements other Calcium-Binding Proteins, with a Note on Rat and Human

et al. 2012

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“…Somehow paradoxically, MYCN overexpression might also lead to apoptosis and/or sensitize cells to death [8], [9], [10]. Indeed, MNA NBs are sensitive to chemo- or radiotherapy at diagnosis, and MNA or MYCN overexpressing NB cell lines are more sensitive to apoptosis induced by DNA damaging agents as compared to MYCN single copy (MNSC) cells [11], [12].…”

Section: Introductionmentioning

confidence: 99%

Galectin-3 Impairment of MYCN-Dependent Apoptosis-Sensitive Phenotype Is Antagonized by Nutlin-3 in Neuroblastoma Cells

et al. 2012

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MYCN amplification occurs in about 20–25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage and impairment of metastasis in xenograft models. Here we report that Galectin-3 impairs MYCN-primed and HIPK2-p53-dependent apoptosis in neuroblastoma cells. Galectin-3 is broadly expressed in human neuroblastoma cell lines and tumors and is repressed by MYCN to induce the apoptosis-sensitive phenotype. Despite its reduced levels, Galectin-3 can still exert residual antiapoptotic effects in MYCN amplified neuroblastoma cells, possibly due to its specific subcellular localization. Importantly, Nutlin-3 represses Galectin-3 expression, and this is required for its potent cell killing effect on MYCN amplified cell lines. Our data further characterize the apoptosis-sensitive phenotype induced by MYCN, expand our understanding of the activity of MDM2-p53 antagonists and highlight Galectin-3 as a potential biomarker for the tailored p53 reactivation therapy in patients with high-risk neuroblastomas.

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“…MYCN overexpression is also directly linked to apoptosis in cell cultures and animal models (12)(13)(14). A largely validated cell system for conditional MYCN overexpression, the SHEP Tet21/N, has extensively been used to show that MYCN sensitizes MYCN single-copy (MNSC) neuroblastoma cells to apoptosis (15,16).…”

Section: Introductionmentioning

confidence: 99%

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Petroni

Veschi

Prodosmo

et al. 2011

Molecular Cancer Research

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MYCN amplification occurs in approximately 20% of human neuroblastomas and is associated with early tumor progression and poor outcome, despite intensive multimodal treatment. However, MYCN overexpression also sensitizes neuroblastoma cells to apoptosis. Thus, uncovering the molecular mechanisms linking MYCN to apoptosis might contribute to designing more efficient therapies for MYCN-amplified tumors. Here we show that MYCN-dependent sensitization to apoptosis requires activation of p53 and its phosphorylation at serine 46. The p53 S46 kinase HIPK2 accumulates on MYCN expression, and its depletion by RNA interference impairs p53 S46 phosphorylation and apoptosis. Remarkably, MYCN induces a DNA damage response that accounts for the inhibition of HIPK2 degradation through an ATM-and NBS1-dependent pathway. Prompted by the rare occurrence of p53 mutations and by the broad expression of HIPK2 in our human neuroblastoma series, we evaluated the effects of the p53-reactivating compound Nutlin-3 on this pathway. At variance from other tumor histotypes, in MYCN-amplified neuroblastoma, Nutlin-3 further induced HIPK2 accumulation, p53 S46 phosphorylation, and apoptosis, and in combination with clastogenic agents purged virtually the entire cell population. Altogether, our data uncover a novel mechanism linking MYCN to apoptosis that can be triggered by the p53-reactivating compound Nutlin-3, supporting its use in the most difficult-to-treat subset of neuroblastoma.

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Increased progenitor proliferation and apoptotic cell death in the sensory lineage of mice overexpressing N-myc

Cited by 5 publications

References 40 publications

Secretagogin is Expressed in Sensory CGRP Neurons and in Spinal Cord of Mouse and Complements other Calcium-Binding Proteins, with a Note on Rat and Human

Secretagogin is Expressed in Sensory CGRP Neurons and in Spinal Cord of Mouse and Complements other Calcium-Binding Proteins, with a Note on Rat and Human

Galectin-3 Impairment of MYCN-Dependent Apoptosis-Sensitive Phenotype Is Antagonized by Nutlin-3 in Neuroblastoma Cells

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

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