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)

Oncogene dosage and expression were studied in 16 testicular neoplasms, 14 of germ cell and two of non-germ cell origin. In comparison with normal DNA, tumour DNA of a total of eight patients (seven with germ cell neoplasm and one with testicular lymphoma) showed increased dosages of KRAS2, PDGFA, EGFR, MET and PDGFB. The most frequent (occurring in six tumours) and prominent (up to 3-4-fold) increases were detected in the dosages of KRAS2 (on chromosome 12p) and PDGFA (chromosome 7p), relative to a reference locus from chromosome 2. Importantly, there was a similar increase in 12p dosage in general in these tumours, suggesting the presence of the characteristic isochromosome 12p marker. On the contrary, possible 7p polysomy (assessed by molecular methods) did not explain the PDGFA (or EGFR) changes in all cases. NRAS, MYCN, CSFIR, MYB, MYC, ABL, HRASI, TP53, and ERBB2 did not reveal any consistent alterations in tumour DNA. In RNA dot blot assays the expression of KRAS2, PDGFA, EGFR, or MYC was generally not increased in the tumour samples when compared to that in normal testicular tissue of the same patients although there was interindividual variation in mRNA levels. It thus appears that while oncogene dosage changes occur in a proportion of testis cancers, they are often part of changes in large chromosomal regions or whole arms and are seldom accompanied by altered expression.
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PMID:Oncogenes in human testicular cancer: DNA and RNA studies. 182 52

Chronic myelogenous leukemia (CML) is the best understood human cancer. The molecular basis of CML involves activation of a cellular proto-oncogene--ABL. The consequence is to increase tyrosine kinase activity. This results in a marked clonal increase in the myeloid mass. Later on, cellular maturation is blocked and the decrease eventuates in acute leukemia. Abnormalities of other proto-oncogenes or antioncogenes, like P53, may be involved in leukemia progression. Treatment of CML involves chemotherapy and, more recently, interferon. Whether this treatment prolongs survival or increases the likelihood of cure is unknown but either result seems unlikely. Bone marrow transplants which cure about 50% of persons with CML are most effective when performed in chronic phase.
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PMID:Chronic myelogenous leukemia: molecule to man. 189 3

Chronic myelogenous leukemia (CML) is characterized cytogenetically by the presence of the Philadelphia chromosome, which is the result of a reciprocal translocation between chromosomes 9 and 22. Analysis of the rearranged chromosome 22 have demonstrated that the DNA breakpoints fall within a 5.8-kilobase (kb) region termed M-bcr. In Ph1-acute lymphocytic leukemia, approximately half of the patients have a breakpoint within M-bcr, whereas the remaining half have the break within the first intron of the BCR gene (m-bcr). We have investigated five cases with CML in the blastic phase to search the molecular mechanism of blastic crisis in CML. Using a method of reverse transcriptase-polymerase chain reaction (RT-PCR), we have identified both types of breakpoints in samples of the three cases, suggesting the existence of M-bcr/ABL and m-bcr/ABL chimeric mRNAs in the RNA samples derived from blasts of the three cases. We have further analysed for alterations in the p53 gene in those cases. The p53 gene is now considered to be a tumor suppressor gene and its mutations play a role in the development of many human malignancies. We have attempted to determine whether the p53 gene is involved in the mechanism of blastic crisis in CML. Using the methods of RT-PCR and single stand-conformational polymorphism (SSCP), we have detected expression of only a mutated p53 allele in a case with CML blastic crisis, indicating that inactivation of the p53 gene in both alleles may contribute to the blastic crisis in this case. Accumulation of molecular analysis in more cases will clarify the mechanism of blastic crisis in CML.
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PMID:[Analysis of Ph1-positive leukemia by PCR]. 206 73

The BCR gene (Groffen et al., 1984) plays a critical role in the pathogenesis of human leukemias that involve the Philadelphia chromosome (Ph1) (Rowley, 1973; Nowell & Hungerford, 1960). Cells containing the Ph1 contain a chimeric gene formed from the fusion of BCR (Collins et al., 1987; Lifshitz et al. 1988) and ABL genes that results from the reciprocal translocation of segments of chromosomes 9 and 22 (Shtivelman et al., 1985). The product of this chimera is a 210 kDa protein, termed P210 BCR-ABL, that possesses an activated tyrosine kinase activity (Konopka et al., 1984; Kloetzer et al., 1985). Studies using long-term marrow culture systems and retrovirus-mediated gene transfer have documented that P210 BCR-ABL can stimulate the growth of immature hematopoietic precursor cell types (McLaughlin et al., 1987; Young & Witte, 1984). We have previously reported that P210 BCR-ABL exists in cytoplasmic complexes in association with a 53 kDa protein termed ph-P53 (Maxwell et al., 1987; Li et al. 1988). Similarly, BCR proteins have been found in cytoplasmic complexes containing ph-P53 in cells lacking the Ph1 (Li et al., 1989). These BCR protein complexes possess an associated ser/thr protein kinase activity. In this same study, we found that P210-containing complexes phosphorylate BCR proteins on tyrosine residues in vitro (Li et al., 1989). We now present results which demonstrate that P210 BCR-ABL is tightly associated with P160 BCR and ph-P53 proteins in cytoplasmic complexes from cells containing the Ph1.
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PMID:P210 BCR-ABL is complexed to P160 BCR and ph-P53 proteins in K562 cells. 214 May 98

A critical determinant of the efficacy of antineoplastic therapy is the response of malignant cells to DNA damage induced by anticancer agents. The p53 tumor-suppressor gene is a critical component of two distinct cellular responses to DNA damage, the induction of a reversible arrest at the G1/S cell cycle checkpoint, and the activation of apoptosis, a genetic program of autonomous cell death. Expression of the BCR-ABL chimeric gene produced by a balanced translocation in chronic myeloid leukemia, confers resistance to multiple genotoxic anticancer agents. BCR-ABL expression inhibits the apoptotic response to DNA damage without altering either the p53-dependent WAF1/CIP1-mediated G1 arrest or DNA repair. BCR-ABL-mediated inhibition of DNA damage-induced apoptosis is associated with a prolongation of cell cycle arrest at the G2/M restriction point; the delay of G2/M transition may allow time to repair and complete DNA replication and chromosomal segregation, thereby preventing a mitotic catastrophe. The inherent resistance of human cancers to genotoxic agents may result not only by the loss or inactivation of the wild-type p53 gene, but also by genetic alterations such as BCR-ABL that can delay G2/M transition after DNA damage.
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PMID:BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. 762 Jan 67

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of the myeloid lineage. It has a progressive course typified by the transition from the chronic phase to the accelerated phase and on to blast crisis. The hallmark of CML is the translocation between chromosomes 9 and 22 that results in the chimeric BCR-ABL gene encoding p210BCR-ABL. The oncogenic potential of this protein has been validated, and it is believed that it contributes in a critical way to the initiation of CML. However, the secondary genetic forces responsible for the transition from the chronic state to the fully blastic stage are not clear. Evidence for chromosomal instability includes the clonal evolution which characterizes advanced CML. In regard to specific genetic aberrations, sporadic reports have shown alterations in H-RAS, c-MYC, retinoblastoma, and P53 genes, as well as production of p190BCR-ABL during the progression of CML. In addition, we have recently found evidence for excessive interleukin-1 beta production, acting in an autocrine and/or paracrine manner, in the more advanced stages of the disease. Taken together, current data suggest that multiple molecular pathways lead to disease progression, and that distinct subsets of genetic alterations exist in blast crisis patients.
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PMID:CML: mechanisms of disease initiation and progression. 825 16

Alterations in the tumor suppressor gene p53 are associated with the pathogenesis of blastic transformation of chronic myeloid leukemia (CML), but their exact role, particularly their relationship with the chimeric protein p210BCR/ABL, is poorly defined. Point mutations in p53 have been found in some cases of blast crisis and CML blastic cell lines, but it is not clear whether complete inactivation of p53 tumor suppressor function, with or without the production of a mutant protein, can by itself trigger the process of blastic transformation. By using retroviral gene transfer, we showed that the introduction of a mutant human p53 cDNA into hematopoietic progenitor cells from patients with CML in chronic phase, which already contain p210BCR/ABL, could promote their proliferation in vitro, and occasionally even lead to the growth of factor-independent colonies. We conclude that a mutant p53 may act in synergy with p210BCR/ABL and promote the survival and proliferation of CML hematopoietic stem and progenitor cells in vitro.
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PMID:Retroviral transduction of Philadelphia-positive chronic myeloid leukemia cells with a human mutant p53 cDNA and its effect on in vitro proliferation. 828 58

The actual significance of the type of BCR-ABL rearrangement in chronic myeloid leukemia (CML) prognosis remains controversial. Also, the molecular events that lead to CML progression are largely unknown. We analyzed the M-BCR breakpoint position in 64 CML patients by Southern blot and correlated the molecular findings with the cytogenetic, hematologic, and clinical data. No statistically significant differences were found with respect to the clinical and hematologic data presented at diagnosis or in the median duration of chronic phase (CP) and survival between the groups of patients with 5' and 3' breakpoints. We also studied by PCR-SSCP and direct sequencing the p53 gene in patients with specimens available in both chronic phase and blast crisis. We identified p53 mutations in 17% of the blast crisis samples analyzed, whereas no abnormalities were found in CP. This finding suggests that only in a minor fraction of cases are lesions in the p53 gene involved in transformation. Given the present findings, along with previous reports, we believe that a novel mechanism to explain the heterogeneity of CML should be postulated and actively pursued, as should the identification of secondary molecular events more consistently involved in progression.
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PMID:Further evidence for the lack of correlation between the breakpoint site within M-BCR and CML prognosis and for the occasional involvement of p53 in transformation. 853 22

Chronic myeloid leukaemia (CML) is characterized cytogenetically by a t(9;22)(q34;ql1) reciprocal translocation which gives origin to a hybrid BCR-ABL gene, encoding a p2lO(BCR-ABL) fusion protein with elevated tyrosine kinase activity and transforming abilities. The t(9;22) was suggested to be associated with genomic imprinting of centromeric regions of chromosomes 9 and 22, but the genes directly affected by the translocation, ABL and BCR, were shown not to be imprinted. For most diagnostic and research purposes the BCR-ABL gene can be efficiently identified by reverse-transcription and polymerase chain reaction (RT/PCR) amplification of its fusion transcripts, which can be quantified by competitive PCR and similar assays for assessment of residual disease in the follow-up of therapy. In the great majority of CML patients the BCR-ABL transcripts exhibit a b2a2 and/or a b3a2 junction; in rare cases, the only detectable BCR-ABL transcripts have unusual junctions, such as b2a3, b3a3, e1a2 or e6a2. There is a recent suggestion that the BCR-ABL gene may not be always 'functional', since extremely low levels of BCR-ABL transcripts can be found in leucocytes from normal individuals and, conversely, it appears that no BCR-ABL transcription can be detected in a proportion of Ph-positive haematopoietic progenitors from some CML patients. The role, if any, of the reciprocal ABL-BCR hybrid gene in CML is unknown. Although its mRNA message is in frame, no ABL-BCR fusion protein has yet been identified in CML patients. The blast crisis of CML has been variably associated with abnormalities of proto-oncogenes, such as RAS and MYC, or of tumour suppressor genes, in particular RB, p53 and p16, or with the generation of chimeric transcription factors, as in the AML1-EVI1 gene fusion. It is likely, therefore, that multiple and alternative molecular defects, as opposed to a single universal mechanism, underlie the acute transformation of the disease.
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PMID:The molecular biology of chronic myeloid leukaemia. 865 67

Blastic transformation of chronic myelogenous leukemia (CML) is characterized by the presence of nonrandom, secondary genetic abnormalities in the majority of Philadelphia1 clones, and loss of p53 tumor suppressor gene function is a consistent finding in 25-30% of CML blast crisis patients. To test whether the functional loss of p53 plays a direct role in the transition of chronic phase to blast crisis, bone marrow cells from p53+/+ or p53-/- mice were infected with a retrovirus carrying either the wild-type BCR/ABL or the inactive kinase-deficient mutant, and were assessed for colony-forming ability. Infection of p53-/- marrow cells with wild-type BCR/ABL, but not with the kinase-deficient mutant, enhanced formation of hematopoietic colonies and induced growth factor independence at high frequency, as compared with p53+/+ marrow cells. These effects were suppressed when p53-/- marrow cells were coinfected with BCR/ ABL and wild-type p53. p53-deficient BCR/ABL-infected marrow cells had a proliferative advantage, as reflected by an increase in the fraction of S+G2 phase cells and a decrease in the number of apoptotic cells. Immunophenotyping and morphological analysis revealed that BCR/ABL-positive p53-/- cells were much less differentiated than their BCR/ABL-positive p53+/+ counterparts. Injection of immunodeficient mice with BCR/ABL-positive p53-/- cells produced a transplantable, highly aggressive, poorly differentiated acute myelogenous leukemia. In marked contrast, the disease process in mice injected with BCR/ABL-positive p53+/+ marrow cells was characterized by cell infiltrates with a more differentiated phenotype and was significantly retarded, as indicated by a much longer survival of leukemic mice. Together, these findings directly demonstrate that loss of p53 function plays an important role in blast transformation in CML.
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PMID:Blastic transformation of p53-deficient bone marrow cells by p210bcr/abl tyrosine kinase. 891 57


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