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)

An in vitro model of folate-deficient erythropoiesis has been developed using proerythroblasts isolated from the spleens of Friend virus-infected mice fed an amino acid-based, folate-free diet. Control proerythroblasts were obtained from Friend virus-infected mice fed the same diet plus 2 mg folic acid/kg diet. Our previous studies showed that, after 20 to 32 hours of culture in folate-deficient medium with 4 U/mL of erythropoietin, the folate-deficient proerythroblasts underwent apoptosis, whereas control erythroblasts survived and differentiated into reticulocytes over a period of 48 hours. The addition of folic acid or thymidine to the folate-deficient medium prevented the apoptosis of the folate-deficient erythroblasts, thereby implicating decreased thymidylate synthesis as the main cause of apoptosis in the folate-deficient erythroblasts. In the study reported here, we examined intracellular folate levels, uracil misincorporation into DNA, p53 and p21 proteins, and reticulocyte formation in erythroblasts cultured in folate-deficient or control medium. In all experiments, the folate-deficient erythroblasts cultured in folate-deficient medium gave results that varied significantly from folate-deficient erythroblasts cultured in control medium or control erythroblasts cultured in either folate-deficient or control media. Folate-deficient erythroblasts cultured in folate-deficient medium had marked decreases in all coenzyme forms of folate that persisted throughout culture, increased uracil misincorporation into DNA, persistent accumulations of p53 and p21, and decreased reticulocyte production but increased size of individual reticulocytes. A model of folate-deficient erythropoiesis based on apoptosis of late stage erythroblasts is presented. This model provides explanations for the clinical findings in megaloblastic anemia.
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PMID:Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production. 919 87

Deficiency of folate or vitamin B(12) (cobalamin) causes megaloblastic anemia, a disease characterized by pancytopenia due to the excessive apoptosis of hematopoietic progenitor cells. Clinical and experimental studies of megaloblastic anemia have demonstrated an impairment of DNA synthesis and repair in hematopoietic cells that is manifested by an increased percentage of cells in the DNA synthesis phase (S phase) of the cell cycle, compared with normal hematopoietic cells. Both folate and cobalamin are required for normal de novo synthesis of thymidylate and purines. However, previous studies of impaired DNA synthesis and repair in megaloblastic anemia have concerned mainly the decreased intracellular levels of thymidylate and its effects on nucleotide pools and misincorporation of uracil into DNA. An in vitro model of folate-deficient erythropoiesis was used to study the relationship between the S-phase accumulation and apoptosis in megaloblastic anemia. The results indicate that folate-deficient erythroblasts accumulate in and undergo apoptosis in the S phase when compared with control erythroblasts. Both the S-phase accumulation and the apoptosis were induced by folate deficiency in erythroblasts from p53 null mice. The complete reversal of the S-phase accumulation and apoptosis in folate-deficient erythroblasts required the exogenous provision of specific purines or purine nucleosides as well as thymidine. These results indicate that decreased de novo synthesis of purines plays as important a role as decreased de novo synthesis of thymidylate in the pathogenesis of megaloblastic anemia.
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PMID:Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism. 1105 10

Folate is a critical factor for DNA metabolism and its deficiency is associated with a number of human diseases and cancers. Although it has been shown that folate deficiency induces genomic instability and apoptotic cell death, the underlying mechanism is largely unknown. Given the role of mismatch repair in maintaining genomic integrity, mismatch repair was tested for its involvement in folate deficiency-induced genomic instability and cell death. Cells proficient in mismatch repair were highly sensitive to folate deficiency compared with cells defective in either hMutSalpha or hMutLalpha. Since wild-type cells but not mutant cells underwent apoptosis upon extensive folate depletion, the apoptotic response is dependent on a functional mismatch repair system. Our data also indicate that p53 is required for the folate depletion-induced apoptosis. In vitro biochemical studies demonstrated that hMutSalpha specifically recognized DNA damage induced by folate deficiency, suggesting a direct participation of mismatch repair proteins in mediating the apoptotic response. We conclude that while the mismatch repair-dependent apoptosis is necessary to protect damaged cells from tumorigenesis, it may damage a whole tissue or organ, as seen in patients with megaloblastic anemia, during extensive folate deficiency.
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PMID:Involvement of DNA mismatch repair in folate deficiency-induced apoptosis small star, filled. 1208 1

Cyanocobalamin (Vitamin B12, VB12) and Folic acid (Vitamin B9, VB9) deficiency leads to anemia in women. We have recently shown low VB12 and VB9 levels in the serum of megaloblastic anemia (MBA) patients. Further, our study demonstrated elevated homocysteine and p53, respectively, in the serum and bone marrow aspirates of MBA patients but not in non-MBA subjects. However, it is unknown whether any gender specific variation in VB12 and VB9 level exists in MBA and non-MBA patients? In addition, it is unclear whether low VB12 and VB9 has a role in the regulation of p53 expression in MBA patients? And whether elevated p53 is functionally active? If so, does bone marrow aspirates of MBA patients show elevated apoptosis. Hence, we have analyzed VB12 and VB9 levels in MBA patients and compared with non-MBA subjects. Next, methylation status of p53 promoter was determined and correlated with p53 expression. Furthermore, the level of apoptosis in bone marrow aspirate paraffin blocks was estimated using TUNEL staining. In conclusion, low VB12 and VB9 in male and female patients directly correlate with p53 promoter unmethylation status, but, inversely correlate with p53 protein expression and its activity, only in MBA cases but not in non-MBA controls.
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PMID:Unmethylated promoter DNA correlates with p53 expression and apoptotic levels only in Vitamin B9 and B12 deficient megaloblastic anemia but not in non-megaloblastic anemia controls. 2924 73

Per the revised fourth edition World Health Organization classification of acute myeloid leukemia, pure erythroid leukemia is now the sole type of acute erythroid leukemia. The diagnosis of this rare entity is often challenging and the cytologic overlap with non-neoplastic (eg, megaloblastic anemia) and neoplastic entities (eg, other types of acute leukemia and non-hematopoietic malignancies) warrants a significant degree of clinical, laboratory, immunophenotypic, and genetic investigation. Given the limited number of reports of this rare and diagnostically challenging entity, we report detailed clinicopathologic characteristics from 15 patients, the largest series thus far, of primary de novo pure erythroid leukemia to provide further diagnostic insights into this entity and reveal strategies for making the diagnosis. We found that de novo pure erythroid leukemia is a disease of adults (median age 68 years), exhibits a striking male predominance, is universally associated with an abnormal karyotype and has an exceedingly poor overall median survival of 1.4 months. Given the general inability of immunophenotypic markers to discriminate neoplastic from non-neoplastic erythroid proliferations, key features identified in this study to help establish the diagnosis of pure erythroid leukemia and exclude mimickers include circulating pronormoblasts, clear-cut dysplasia in erythroid, granulocytic, and/or megakaryocytic lineage, utilization of a broad immunophenotypic panel, TP53 immunohistochemical positivity, and identification of a complex, often highly complex, karyotype. Given the gravity of a diagnosis of de novo pure erythroid leukemia, it should be rendered with utmost confidence.
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PMID:De novo pure erythroid leukemia: refining the clinicopathologic and cytogenetic characteristics of a rare entity. 2932 15

The pathogenesis of megaloblastic hemopathies (MH) is centered on the deficiency of vitamin B12 and folic acid with interruption of erythrocyte maturation. This study researched the participation of p53 and p21 in the pathophysiology of the disease. A retrospective study enrolled 95 patients with histopathologic diagnosis by biopsy or bone marrow clot (BMB/BMC), with clinical review and immunohistochemical study in tissue microarray (TMA) for p53 and p21, detailing their marking location. All patients had BMC and only 11 had BMB. The CMO was a differential of this study and it allowed an expanded sample. In the TMA, 63.7% (58/91) of the samples were immunopositive for p53; and 35.2% (31/88) were immunopositive for p21. Nuclear staining, divergent from the literature, was observed in 17.3% (10/58) among those p53+ and in 38.7% (12/31) among those p21+. The pattern of immunostaining showed non-significant differences (P=0.474) regarding morphologic and clinical aspects. The positivity for both may indicate an effective balance between apoptosis and anti-apoptotic action. Excessive inhibition of apoptosis would contribute to high global cellularity, but without functional maturation effectiveness. In conclusion, there is p21 and/or p53 immunoexpression in most cases of this study and there is no clear association between immunoexpression pattern and patient outcome. Unlike the literature, we also found a percentage of nuclear immunostaining, but the finding was not statistically significant. Combination of p21 and p53 results created different possibilities of pathologic interpretation for MH, reinforcing the importance of studies similar to this one.
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PMID:p53 and p21 expression in bone marrow clots of megaloblastic anemia patients. 3278 11