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)

Downregulation of p53 is associated with most of the neoplasms, however it claims additional significance for hematopoietic malignancy due to its supplementary role during hematopoiesis. Apart from the classical role as tumor suppressor, p53 during steady state hematopoiesis is associated with the maintenance of quiescent cell population in bone marrow by upregulating necdin (Ndn) and Gfi-1. We felt, it is necessary to delineate its attribution towards malignant conversion of hematopoietic system during leukemogenesis from all the possible angles. The present study deals with the characterization of N-N' Ethylnitrosourea (ENU) induced mouse model of leukemia by peripheral blood hemogram, bone marrow cytology, histology, cytochemical staining (MPO) and scanning electron microscopic study. We further investigated the alteration of conventional and hematopoiesis specific p53 pathways by flowcytometric expressional analysis of ATM, Chk-2, p53, p21, Ndn, Gfi-1 and Tie-2. The disruption of classical p53 pathway was observed in leukemic hematopoietic stem/progenitor population which involved downregulation of ATM, Chk-2, p53 and p21. Moreover, the expressional decline of Ndn and Gfi-1 hinted towards the mechanism of hindrance of hematopoietic quiescency in leukemic bone marrow. Increased expression of Tie-2 due to reverse correlation with p53 was found to be responsible for pathological angiogenesis in bone marrow together with increased blast burden in bone marrow during leukemia. The study presents the mechanistic scenario of the alteration of both classical as well as hematopoiesis specific p53 pathways in HSPC compartment triggering leukemic pathophysiology.
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PMID:Alteration of classical and hematopoiesis specific p53 pathway in the bone marrow hematopoietic stem/progenitor compartment facilitates leukemia progression in experimental mice. 2728 Apr 87

Endometrial stromal tumors include translocation-associated low- and high-grade endometrial stromal sarcomas (ESS) and highly malignant undifferentiated uterine sarcomas (UUS). UUS is considered a poorly defined group of aggressive tumors and is often seen as a diagnosis of exclusion after ESS and leiomyosarcoma (LMS) have been ruled out. We performed a comprehensive analysis of gene expression, copy number variation, point mutations, and immune cell infiltrates in the largest series to date of all major types of uterine sarcomas to shed light on the biology of UUS and to identify potential novel therapeutic targets. We show that UUS tumors have a distinct molecular profile from LMS and ESS. Gene expression and immunohistochemical analyses revealed the presence of high numbers of tumor-associated macrophages (TAMs) in UUS, which makes UUS patients suitable candidates for therapies targeting TAMs. Our results show a high genomic instability of UUS and downregulation of several TP53-mediated tumor suppressor genes, such as NDN, CDH11, and NDRG4. Moreover, we demonstrate that UUS carry somatic mutations in several oncogenes and tumor suppressor genes implicated in RAS/PI3K/AKT/mTOR, ERBB3, and Hedgehog signaling.
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PMID:Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas. 2857 Feb 76

Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia-initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations.
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PMID:Necdin modulates leukemia-initiating cell quiescence and chemotherapy response. 2915 5

Necdin, a growth suppressor expressed predominantly in postmitotic neurons, interacts with transcription factors E2F1 and p53. Mitochondrial dysfunction plays central roles in the pathophysiology of neurodegenerative disease including Parkinson's disease. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-la) is master regulator in mitochondrial biogenesis. Necdin promotes neuronal mitochondrial biogene- sis induced by enhanced PGC-la expression in neuron. Necdin binds and strongly stabilizes PGC-la by inhibiting its ubiquitin-proteasomal degradation. Necdin KO mice aggravates MPTP-induced dopaminergic neuronal loss. In the adult mice, AAV-mediated overexpression of necdin in the substantia nigra leads to significant neuroprotection in experimental Parkinson's disease. These findings demonstrate that necdin promotes mitochondrial biogenesis mediated by stabilization of endogenous PGC-la protein to enhance neuroprotection against neurodegenerative disease by mitochondriallInsults.
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PMID:Neuroprotective effects of Necdin in the Parkinson's disease. 3056 92

Aplastic anemia is the bone marrow failure condition characterized by the development of hypocellularity in both marrow and peripheral blood compartments. Anti-tumor chemotherapeutic agents often exert secondary effect on hematopoietic system leading to aplastic anemia by marrow failure. The precise mechanisms behind the marrow ablative effects of the drugs remain yet to be established. The present study holds a mechanistic approach to unveil the mystery. Aplastic anemia was generated in mice with the administration of busulfan and cyclophosphamide followed by the characterization of the disease with peripheral blood hemogram, histopathological and cytochemical examinations of bone marrow. To gain deep knowledge about the molecular mechanisms of the hematopoietic disruption, cytotoxicity assay, DNA damage measurement, apoptosis study, replicative senescence analysis, redox balance study, mitochondrial membrane potential change assessment, flowcytometric expressional analysis of p21, p53, ATM, Chk-2, Necdin, Gfi-1, c-myc, KU-80 and Sod-2 were done with marrow hematopoietic stem/ progenitor cells (HSPCs). Severe blood pancytopenia and marrow hypocellularity was found in aplastic mice. Proliferative hindrance and apoptosis of marrow cells were identified as the cause behind the hematopoietic catastrophe. The genotoxic effects of the drugs triggered chromatin damage and induced replicative senescence in aplastic HSPCs by upregulating p21 in a p53 independent manner. Moreover, accumulation of genomic insults also caused apoptotic elimination of marrow cells due to disruption of mitochondrial membrane potential by generating redox imbalance. The study established the underlying mechanisms behind hematopoietic disruption during drug induced marrow aplasia. Outcome of the study may be helpful in successful designing of therapeutic strategies for the disease concerned.
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PMID:Genomic insult oriented mitochondrial instability and proliferative hindrance in the bone marrow of aplastic mice including stem/progenitor population. 3068 72


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