loading...| Preferred Name |
Medulloblastoma |
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| Synonyms |
Organ_System: nervous system PathwayType: signaling CellType: cancer cell CellType: neural stem cell Organ: brain PMID: 20581434 PMID: 20414201 Tissue: nerve tissue PMID: 16290230 PMID: 22430388 NodeType: Pathway PMID: 18676356 Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Notes: Headnote: Medulloblastoma is a tumor that arises from stem and/or progenitor cells of the cerebellum and is the most common brain tumor affecting children. Signaling description: The central pathways involved in medulloblastoma pathogenesis are Sonic hedgehog homolog (SHH), WNT, Notch, ERBB, BMP, and IGF/PI3K signaling. In the SHH pathway, binding of SHH to its receptor (PTCH1) relieves inhibition on the downstream effector SMO and allows the release of GLI from inhibitory protein, SUFU. Inactivating mutations of PTCH1 and SUFU and/or activating mutations of SMO have been found in 15-30% of sporadic medulloblastomas. Additionally, germline mutations in PTCH1 cause Gorlin syndrome (basal cell nevus syndrome). Further, in WNT pathway, WNT3A ligand binds to its receptor (FZD) leading to the release of its downstream effector beta-catenin (CTNNB1) from an inhibitory complex that includes APC and AXIN1/2 proteins. Subsequent nuclear accumulation of CTNNB1 is thought to mediate its tumorigenic functions through the activation of TCF7/LEF1 transcription factors. Approximately 20% of sporadic medulloblastomas have mutations in APC, AXIN1/2, or CTNNB1. APC mutations are found in Turcot syndrome, which has a predisposition to medulloblastoma development. In addition, TP53 may be silenced due to mutations in medulloblastoma. TP53 mutations are typical for Li-Fraumeni syndrome, which has a high incidence of medulloblastoma development. Furthermore, Notch1/2/3 are overexpressed in a subset of medulloblastomas. Also, ERBB is important in regulating the development of the neuronal tissue. ERBB2 and ERBB4 are overexpressed in medulloblastoma and are able to activate the PI3K/AKT1 signaling. ERBB2 is overexpressed in 28% of medulloblastoma cases. Additionally, deletion mutants of ERBB4 have been found in childhood medulloblastomas. The IGF system also plays an important role in neuronal development and is involved in the development of brain tumors. Most medulloblastomas overexpress IGF1, IGF2, and IGF1R proteins. Outcome effects: The downstream targets of SHH are BMI1, CCND1/2, SOX2, NANOG, and others. Further, TCF7/LEF1 transcription factors activate MYC, OTX2, REST, and SOX4/11 target genes, which have established roles in cellular proliferation, block of differentiation, and inhibition of apoptosis (MYC, MYCN, and MNT may be overexpressed in medulloblastoma due to activating mutations/amplifications). Also, the up-regulation of Notch signaling activates the HES1/5 transcription factors, which negatively regulate the differentiation of neural progenitor cells. The, ERBB2 is thought to promote tumorigenesis by promoting the expression of pro-metastatic genes such as S100A4 and CCL5. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PMID: 21243257 Description: Medulloblastoma arises from stem and/or progenitor cells of the cerebellum and is the most common brain tumor affecting children. Pathway is built manually using published studies. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-f116e34c-a226-42f4-84de-37e046996ead PMID: 22134537 Source: Diseases |
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| ID |
urn:agi-pathway:uuid-f116e34c-a226-42f4-84de-37e046996ead |
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| database_cross_reference |
PS:PathwayType PS:Description PS:Tissue PS:Pathway_Author PS:Link PS:CellType PS:Organ_System PS:PMID PS:NodeType PS:Notes PS:Organ PS:Source |
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| has_exact_synonym |
Organ_System: nervous system PathwayType: signaling CellType: cancer cell CellType: neural stem cell Organ: brain PMID: 20581434 PMID: 20414201 Tissue: nerve tissue PMID: 16290230 PMID: 22430388 NodeType: Pathway PMID: 18676356 Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin Notes: Headnote: Medulloblastoma is a tumor that arises from stem and/or progenitor cells of the cerebellum and is the most common brain tumor affecting children. Signaling description: The central pathways involved in medulloblastoma pathogenesis are Sonic hedgehog homolog (SHH), WNT, Notch, ERBB, BMP, and IGF/PI3K signaling. In the SHH pathway, binding of SHH to its receptor (PTCH1) relieves inhibition on the downstream effector SMO and allows the release of GLI from inhibitory protein, SUFU. Inactivating mutations of PTCH1 and SUFU and/or activating mutations of SMO have been found in 15-30% of sporadic medulloblastomas. Additionally, germline mutations in PTCH1 cause Gorlin syndrome (basal cell nevus syndrome). Further, in WNT pathway, WNT3A ligand binds to its receptor (FZD) leading to the release of its downstream effector beta-catenin (CTNNB1) from an inhibitory complex that includes APC and AXIN1/2 proteins. Subsequent nuclear accumulation of CTNNB1 is thought to mediate its tumorigenic functions through the activation of TCF7/LEF1 transcription factors. Approximately 20% of sporadic medulloblastomas have mutations in APC, AXIN1/2, or CTNNB1. APC mutations are found in Turcot syndrome, which has a predisposition to medulloblastoma development. In addition, TP53 may be silenced due to mutations in medulloblastoma. TP53 mutations are typical for Li-Fraumeni syndrome, which has a high incidence of medulloblastoma development. Furthermore, Notch1/2/3 are overexpressed in a subset of medulloblastomas. Also, ERBB is important in regulating the development of the neuronal tissue. ERBB2 and ERBB4 are overexpressed in medulloblastoma and are able to activate the PI3K/AKT1 signaling. ERBB2 is overexpressed in 28% of medulloblastoma cases. Additionally, deletion mutants of ERBB4 have been found in childhood medulloblastomas. The IGF system also plays an important role in neuronal development and is involved in the development of brain tumors. Most medulloblastomas overexpress IGF1, IGF2, and IGF1R proteins. Outcome effects: The downstream targets of SHH are BMI1, CCND1/2, SOX2, NANOG, and others. Further, TCF7/LEF1 transcription factors activate MYC, OTX2, REST, and SOX4/11 target genes, which have established roles in cellular proliferation, block of differentiation, and inhibition of apoptosis (MYC, MYCN, and MNT may be overexpressed in medulloblastoma due to activating mutations/amplifications). Also, the up-regulation of Notch signaling activates the HES1/5 transcription factors, which negatively regulate the differentiation of neural progenitor cells. The, ERBB2 is thought to promote tumorigenesis by promoting the expression of pro-metastatic genes such as S100A4 and CCL5. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. PMID: 21243257 Description: Medulloblastoma arises from stem and/or progenitor cells of the cerebellum and is the most common brain tumor affecting children. Pathway is built manually using published studies. PMID: 22134537 Source: Diseases |
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| id |
urn:agi-pathway:uuid-f116e34c-a226-42f4-84de-37e046996ead |
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| label |
Medulloblastoma |
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| notation |
uuid-f116e34c-a226-42f4-84de-37e046996ead |
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| prefLabel |
Medulloblastoma |
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| treeView |
urn:agi-folder:nerve_tissue urn:agi-folder:m urn:agi-folder:nervous_system urn:agi-folder:medulloblastoma |
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| subClassOf |
urn:agi-folder:nerve_tissue urn:agi-folder:m urn:agi-folder:nervous_system urn:agi-folder:medulloblastoma |