ArticlePloS one2011
The p53 inhibitor MDM2 facilitates Sonic Hedgehog-mediated tumorigenesis and influences cerebellar foliation.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 42 citations in OpenAlex.
- Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target.Cancer cell · 2025Article
- Transcriptomic convergence despite genomic divergence drive field cancerization in synchronous squamous tumors.Frontiers in oncology · 2024Article
- Medulloblastoma and the DNA Damage Response.Frontiers in oncology · 2022Review
- Acupuncture combined with moxibustion promote the recovery of spinal cord injury in correlation with Shh/Gli-1 signaling pathway.The journal of spinal cord medicine · 2022Article
- p53 Function Is Compromised by Inhibitor 2 of Phosphatase 2A in Sonic Hedgehog Medulloblastoma.Molecular cancer research : MCR · 2019Article
- BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation.Cancer cell · 2018Article
- Neuronal Migration During Development of the Cerebellum.Frontiers in cellular neuroscience · 2018Review
- Genipin suppresses colorectal cancer cells by inhibiting the Sonic Hedgehog pathway.Oncotarget · 2017Article
- Inhibition of the CyclinD1 promoter in response to sonic hedgehog signaling pathway transduction is mediated by Gli1.Experimental and therapeutic medicine · 2017Article
- Intracranial undifferentiated malign neuroglial tumor in Smith-Lemli-Opitz syndrome: A theory of a possible predisposing factor for primary brain tumors via a case report.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2017Article
- Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation.eLife · 2016Article
- Differential timing of granule cell production during cerebellum development underlies generation of the foliation pattern.Neural development · 2016Article
- Evasion of cell senescence in SHH medulloblastoma.Cell cycle (Georgetown, Tex.) · 2016Review
- Cerebellum Development and Tumorigenesis: A p53-Centric Perspective.Trends in molecular medicine · 2016Review
- Review
- p63 Sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress.Cell death and differentiation · 2013Article
- The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo.Genes & development · 2013Article
- Pharmacological activation of the p53 pathway by nutlin-3 exerts anti-tumoral effects in medulloblastomas.Neuro-oncology · 2012Article
- HDM2 promotes WIP1-mediated medulloblastoma growth.Neuro-oncology · 2012Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2(puro)), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1(+/-) mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.