Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In urodele amphibians, a critical step in limb regeneration is the cellularization and dedifferentiation of skeletal muscle. In contrast, mammalian skeletal muscle does not undergo this response to injury. We have developed a novel simple, stepwise chemical method to induce dedifferentiation and multipotency in mammalian skeletal muscle. Optimal muscle fiber cellularization was induced by the trisubstituted purine small molecule, myoseverin, compared to colchicine, nocodazole, or myoseverin B. The induction of a proliferative response in the cellulate was found to be a crucial step in the dedifferentiation process. This was achieved by down-regulation of the cyclin-dependent kinase inhibitor, p21 (CDKN 1A, CIP1). p21 was found to be a key regulator of this process, because down-regulation of the cyclin-dependent kinase inhibitors p27 (CDKN1B/KIP1) or p57 (CDKN1C/KIP2) or the tumor suppressor p53 (TP53/LFS1) failed to induce proliferation and subsequent dedifferentiation. Treatment with the small molecule reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine) during this proliferative "window" induced the muscle cellulate to differentiate into non-muscle cell types. This lineage switching was assessed using a relatively stringent approach, based on comparative functional and phenotypic assays of cell-type specific properties. This showed that our chemical method allowed the derivation of adipogenic and osteogenic cells that possessed a degree of functionality. This is the first demonstration that mammalian muscle culture can be induced to undergo cellularization, proliferation, and dedifferentiation, which is grossly similar to the key early steps in urodele limb regeneration. These results, based solely on the use of simple chemical approaches, have implications for both regenerative medicine and stem cell biology.
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PMID:Novel chemically defined approach to produce multipotent cells from terminally differentiated tissue syncytia. 2132 36

The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients' ovarian cancer in three out of six TP53-positive cases. In three out of six patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice. The analysis of the TP53 and PPM1D genes, both intimately involved in chemotherapy-induced and/or age-related clonal hematopoiesis (CH), in 523 patients and 1,053 age-matched female control individuals revealed that CH represents a frequent event following chemotherapy, affecting 26 of the 523 patients enrolled (5.0%). Considering that TP53 mutations may arise from chemotherapy-induced CH, our findings help to avoid false-positive genetic diagnoses of LFS1.
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PMID:Diagnosis of Li-Fraumeni Syndrome: Differentiating TP53 germline mutations from clonal hematopoiesis: Results of the observational AGO-TR1 trial. 3021 91