Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hedgehog (Hh) pathway is highly conserved and required for embryonic patterning and determination. Mutations in the Hh pathway are observed in sporadic tumors as well as under syndromic conditions. Common to these syndromes are the findings of polydactyly/syndactyly and brain overgrowth. The latter is also a finding most commonly observed in the cases of mutations in the PI3K/AKT/mTOR pathway. We have identified novel Hh pathway mutations and structural copy number variations in individuals with somatic overgrowth, macrocephaly, dysmorphic facial features, and developmental delay, which phenotypically closely resemble patients with phosphatase and tensin homolog (PTEN) mutations. We hypothesized that brain overgrowth and phenotypic overlap with syndromic overgrowth syndromes in these cases may be due to crosstalk between the Hh and PI3K/AKT/mTOR pathways. To test this, we modeled disease-associated variants by generating PTCH1 and Suppressor of Fused (SUFU) heterozygote cell lines using the CRISPR/Cas9 system. These cells demonstrate activation of PI3K signaling and increased phosphorylation of its downstream target p4EBP1 as well as a distinct cellular phenotype. To further investigate the mechanism underlying this crosstalk, we treated human neural stem cells with sonic hedgehog (SHH) ligand and performed transcriptional analysis of components of the mTOR pathway. These studies identified decreased expression of a set of mTOR negative regulators, leading to its activation. We conclude that there is a significant crosstalk between the SHH and PI3K/AKT/mTOR. We propose that this crosstalk is responsible for why mutations in PTCH1 and SUFU lead to macrocephaly phenotypes similar to those observed in PTEN hamartoma and other overgrowth syndromes associated with mutations in PI3K/AKT/mTOR pathway genes.
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PMID:Mutations in the sonic hedgehog pathway cause macrocephaly-associated conditions due to crosstalk to the PI3K/AKT/mTOR pathway. 3163 85

Angiomyolipoma is the most common mesenchymal tumour of the kidney, even if for a long time it has been viewed as a hamartoma rather than a neoplasm. It belongs to a family of neoplasms, named PEComa, characterised by the constant presence of perivascular epithelioid cells that co-express smooth muscle and melanogenesis markers. Angiomyolipoma can occur in patients with tuberous sclerosis, a hereditary syndrome due to the alteration of TSC1 or TSC2 genes, or sporadically. Angiomyolipoma and its variants are indolent tumours; however, some epithelioid angiomyolipomas/pure epithelioid PEComas are aggressive, and criteria for malignancy have been proposed to identify those cases. Although typical angiomyolipoma is a straightforward diagnosis, pathologists should be aware of the wide morphological spectrum of its variants which could be tricky in routine clinical practice and could require immunohistochemical analysis for resolution. The differential diagnosis may range from an inflammatory process (for instance xanthogranulomatous pyelonephritis) to the most common renal cancers and sarcomas. The immunoexpression of melanogenesis markers (HMB45 and Melan-A) and cathepsin K is extremely helpful in the majority of cases. Recently, a subset of epithelioid angiomyolipoma/pure epithelioid PEComa harbouring TFE3 gene fusions has been described, raising questions about its relationship with the family of perivascular epithelioid cell tumour. The activation of the mTOR pathway due to genetic alterations of tuberous sclerosis complex in TSC1 or TSC2 genes in angiomyolipoma has also been reported as well as the subsequent therapeutic implications.
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PMID:Angiomyolipoma of the kidney: from simple hamartoma to complex tumour. 3313 98


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