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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The disruption of transcriptional regulatory circuits through the elimination of negative regulatory factors (tumor suppressors), the activation of positive acting factors (oncogenes), or when chimeric proteins result from chromosomal translocations, is likely a key event in multistep tumorigenesis. Here, using the transcription factors E2F and AML-1 as model systems, we discuss the disruption of coordinate transcriptional regulation in oncogenesis. E2F oncogenic signals are released when the pRb tumor suppressor is inactivated, and E2F activation may necessitate the coordinate inactivation of a second tumor suppressor, p53. AML-1 is the target of the (8;21) translocation, found in approximately 15% of acute myeloid leukemia (AML) cases, and the t(12;21), found in up to 30% of childhood B-cell acute lymphoblastic leukemias. The t(8;21) creates a fusion protein between AML-1 and a gene of unknown function, mtg8 (ETO), whereas the t(12;21) fuses the TEL (translocation-ets-leukemia) transcription factor to the N-terminus of AML-1. The inv(16), which is the most frequent anomaly found in AML, also targets AML-1, by fusing the gene that encodes AML-1's heterodimeric partner CBF beta to the smooth muscle myosin heavy chain gene MYHll. Thus, E2F and AML-1 provide excellent models for the disruption of transcriptional regulation in cancer.
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PMID:Indirect and direct disruption of transcriptional regulation in cancer: E2F and AML-1. 883 31

A new cell line (LR10.6) with pre-B cell phenotype has been established from bone marrow cells obtained from a child with B lineage acute lymphoblastic leukemia in complete clinical remission. The line expresses nuclear TdT enzyme, cytoplasmic Ig lambda-chain and membrane mu-chain and other B but no T or myeloid markers. The cells also show activation antigens CD69 and CD71, adhesion molecules CD54, CD50 and CD56 and the tyrosine kinase receptor CD117. No expression of multidrug resistance phenotype MDR-1 is observed on these cells which nevertheless express the transcriptional factor p53 protein in a mutant form. Cytogenetic study shows a translocation t(5;12)(q31;p13) involving breakpoints which contain the growth factor interleukin 3 gene (5q31) and the recently identified TEL/ETV6 gene (12p13). Activation of the cells with phorbol-12 myristate 13-acetate (PMA) up-regulates the expression of the CD69 activation antigen and down-regulates the CD117 molecule. In addition, PMA fails to induce the CD20 B cell antigen.
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PMID:A new human cell line with pre-B cell phenotype and t(5;12). 920 88

Few genes have a proven role in the pathogenesis of myelodysplastic syndromes (MDS). The most common abnormalities involve the RAS genes, most notably the N-RAS gene, and are present in 10% of cases at diagnosis and in 30% to 40% during the course of the disease. Mutations of the p53 are found in 5% to 10% of cases. Mutations of the cFMS genes are less common, abnormalities of the NF1 genes seem to occur only in children, and abnormalities of the RB genes are exceedingly rare. A few instances of t(5;12) or t(3;21) translocation have been demonstrated, and their study has provided evidence that the TEL, EVI1, MDS1, and AML1 genes are involved in some cases of MDS. The presence in MDS of recurrent chromosome 7, 5q, and 20q deletions suggests that these chromosomal segments may bear tumor suppressor genes involved in MDS. The gene(s) involved remain(s) to be identified. Clonality studies have shown that stem cell involvement usually occurs at the myeloid level and that normal multipotent stem cells persist in many patients with MDS. This opens up the promising possibility that transplantation of autologous multipotent stem cells may be an effective therapeutic approach.
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PMID:[Molecular abnormalities and clonality in myelodysplastic syndromes]. 940 79

Cytogenetic abnormalities are seen in approximately 50% of cases of myelodysplastic syndrome (MDS) and 80% of cases of secondary MDS (following chemotherapy or radiotherapy). These abnormalities generally consist of partial or complete chromosome deletion or addition (del5q, -7, +8, -Y, del20q), whereas balanced or unbalanced translocations are rarely found in MDS. Fluorescence hybridization techniques (fluorescence in situ hybridization [FISH], multiplex FISH, and spectral karyotyping) are useful in detecting chromosomal anomalies in cases in which few mitoses are obtained or rearrangements are complex. Ras mutations are the molecular abnormalities most frequently found in MDS, followed by p15 gene hypermethylation, FLT3 duplications, and p53 mutations, but none of these abnormalities are specific for MDS. The rare cases of balanced translocations in MDS have allowed the identification of genes whose rearrangements appear to play a role in the pathogenesis of some cases of MDS. These genes include MDS1-EVI1 in t(3;3) or t(3;21) translocations, TEL in t(5;12), HIP1 in t(5;7), MLF1 in t(3;5), and MEL1 in t(1;3). Genes more frequently implicated in the pathogenesis of MDS cases, such as those involving del5q, remain unknown, although some candidate genes are currently being studied. Cytogenetic and known molecular abnormalities generally carry a poor prognosis in MDS and can be incorporated into prognostic scoring systems such as the International Prognostic Scoring System.
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PMID:Chromosome and molecular abnormalities in myelodysplastic syndromes. 1150 56

To elucidate the reasons why mRNA expression of the LGI1 candidate tumor-suppressor gene was severely reduced in the glioma-derived cell line H4, as demonstrated in a previous study, we performed a cytogenetic analysis of this cell line using conventional methods and fluorescence in situ hybridization (FISH) techniques [spectral karyotyping (SKY), interphase- and chromosome FISH of metaphases (I- and C-FISH)]. Cell line H4 is monoclonal and near triploid (+/-3n). SKY enabled us to detect 24 structural aberrations: unbalanced translocations, n = 12; deletions, n = 10; insertion, n = 1; duplication, n = 1. The results were confirmed by I- and C-FISH analysis using chromosome-specific paints, centromer-specific probes and locus-specific probes for p53, PTEN/MMAC1, LGI1, Cyclin D1, EGR1, ETV6/TEL, AML1, and the genomic region 13q14.3 containing the Rb locus. We found loss of one copy of p53 as well as of one copy of Rb. Complete loss of PTEN/MMAC1 was detected, while all copies of LGI1 and Cyclin D1 were preserved. Interestingly, there was a gain of ETV6/TEL and EGR1, which were each present in quadruplicate. Additionally, the AML1 locus revealed mosaicism of cells with three and four copies, respectively. Additionally, a 5q-chromosome [del(5)(q13q33)] was found, which is one of the common features in hematological malignancies, and der(12)t(1;12) was found, suggesting that there might be an additional ETV6/TEL fusion protein. The combination of SKY, I- and C-FISH demonstrates that the neuroglioma cell line H4 harbors cytogenetic aberrations that are reported to occur in glioma-derived cell lines and additional chromosomal aberrations that have so far not been reported to occur in these cell lines. The complex aberrant karyotype and possibly generation of transcription factors by fusion proteins might be reasons for the impaired mRNA expression of the LGI1 candidate tumor-suppressor gene in cell line H4.
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PMID:Identification of uncommon chromosomal aberrations in the neuroglioma cell line H4 by spectral karyotyping. 1150 11

Mutations in signal transduction molecules, which regulate cell differentiation and proliferation, are involved in the development of leukemia. Aberrations of receptor type tyrosine kinases are known to arise from FLT3 mutations in acute myeloid leukemia (AML) and myelodysplastic syndrome, and c-Kit mutations in mast cell tumors. BCR/ABL found in chronic myelogenous leukemia (CML) is a hallmark of the constitutively active forms of cytoplasmic tyrosine kinases. Downstream of the tyrosine kinase is the RAS GTP-binding protein, and genetic mutations related to this protein have been found in a wide variety of malignant tumors including hematopoietic tumors. In the nucleus, transcription factor-encoding genes are frequently detected as the targets of chromosomal translocations found in specific types of leukemias. For instance, the AML1 gene generates AML1/MTG8 chimera by t (8;21) translocation in AML (M2), AML1/EVI-1 chimera by t (3;21) translocation in blastic crisis of CML, and TEL/AML1 chimera in t (12;21) translocation (pre-B cell type acute lymphoblastic leukemia). Another example of abnormal transcription factors is PML/RAR alpha generated by t (15;17) translocation found in acute promyelocytic leukemia. Mutations or deletions of tumor suppressor genes are frequently found in cell cycle regulators such as p53, RB and p16 genes. Therefore, mutations of any molecules involved in the signal transduction pathways from growth factor receptors to inside the nucleus are thought to contribute to neoplastic transformation of hematopoietic cells.
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PMID:[Molecular mechanisms in leukemogenesis]. 1214 88

To better define the incidence and significance of cryptic chromosome lesions in acute myeloid leukemia (AML), fluorescence in situ hybridization (FISH) studies were performed in interphase cells and, when appropriate, in metaphase cells and in morphologically intact BM smears. Fifty-five adult de novo AML (group A) and 27 elderly AML or AML after myelodysplastic syndrome (AML-MDS) (group B) were tested using probes detecting the following anomalies: -5, -7, +8, deletions of 5q31, 7q31, 12p13/ETV6, 17p13/p53, 20q11. All the patients had a normal karyotype in more than 20 cells and tested negative for the common AML-associated fusion genes. No patient in group A was found to carry occult chromosome anomalies, whereas 8/27 patients in group B (P < 0.0001) showed 5q31 or 7q31 deletion (three cases each), a 17p13/p53deletion or trisomy 8 (one case each) in 33-60% interphase cells. Metaphase cells showed only one hybridization signal at 5q31 (three cases) and 7q31 (one case), whereas two normal signals at 7q31 and chromosome 8 centromeres were seen in two patients with 7q deletion and trisomy 8 in interphase cells. The majority of blast cells (76-94%) carried the chromosome anomaly in all cases; erythroid involvement in a minority of cells was seen in three patients. In group B, the presence of occult chromosome anomalies was associated with exposure to myelotoxic agents in the workplace (5/8 cases vs 3/19, P = 0.026) and with a lower complete remission rate (0/6 patients vs 7/12, P = 0.024). We arrived at the following conclusions: (1) cryptic chromosome deletions in the order of a few hundred kb magnitude may be found in a fraction of elderly AML or MDS-related AML and not in de novo adult AML with normal karyotype; (2) these chromosome lesions are usually represented by submicroscopic rearrangements; (3) they display a specific pattern of cell-lineage involvement arguing in favor of their role in the outgrowth of the leukemic blast cells; (4) they are associated with a history of exposure to myelotoxic agents in the workplace and, possibly, with resistance to induction treatment.
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PMID:Incidence and significance of cryptic chromosome aberrations detected by fluorescence in situ hybridization in acute myeloid leukemia with normal karyotype. 1220 Jun 89

Germ-line mutations (present in all cells) in genes that are crucial for the cell cycle cause cancer only in specific cell lines (e.g. mismatch repair genes in the colon; BRCA1-2 in breast and ovary; other cancers in Bloom syndrome, neurofibromatosis and xeroderma pigmentosum). The mutation rate of genes other than mismatch repair or p53 is the same in colon cancer and in normal cells, indicating that a 'mutator phenotype', increasing the rate of mutations in many genes, is not an essential feature of sporadic cancers; conversely, fusion genes, TEL-AML1/AML1-ETO, typical of leukemia, are 100 times more frequent at birth than in overt leukemia in children, indicating that further selective events are needed to cause malignancy. The devastating impairment of immunity, as in AIDS patients, does not cause cancer other than Kaposi's sarcoma and non-Hodgkin's lymphoma, although immunological control is considered to be an essential mechanism in preventing the spread of cancer cells. These observations suggest that cell-specific additional events are needed to explain carcinogenesis. Carcinogenesis has been traditionally interpreted as the sequence of initiation (mutation) and promotion (clone expansion), with an interesting similarity with the neo-Darwinian theory of evolution, based on a first stage of genetic change (including recombination) and a second stage of selection. I propose that carcinogenesis consists in two general phases (not necessarily stages), i.e. genetic change followed by clone expansion (selective advantage). As in neo-Darwinian theory selection is chiefly represented by the elimination of the less fit, the selection of mutated cells would mainly consist in resistance to apoptosis or other types of 'bottlenecks' that hamper a cell's survival; an example of such a bottleneck is the autoimmunity that induces paroxysmal nocturnal hemoglobinuria in individuals with PIG-A mutations. Cancer rates show great variation in different countries around the world, a variation only marginally explained by genetic differences. More interestingly, migrants change their risk of cancer by adapting to that of the population into which they move: as these changes are not likely to be entirely due to mutagens in the environment, we have to invoke selective pressure over mutated cells to explain them. My theory is that mutated cells adapt to environmental 'niches' better than normal cells, in a 'gene-environment interaction' that involves the history of the genetic changes the cell has undergone and the kind of environment in which it happens to live.
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PMID:Cancer as an evolutionary process at the cell level: an epidemiological perspective. 1253 42

The ETV6 gene is a member of the ETS family of transcription factors and the main target of chromosomal rearrangements affecting chromosome band 12p13. To date, more than 15 fusion partners of ETV6 have been characterized at the molecular level. Most of these fusions encode chimeric proteins with oncogenic properties. However, some of the translocations do not produce a functional fusion protein, but may induce ectopic expression of oncogenes located close to the breakpoint. We herein report the characterization and cloning of a novel cryptic translocation, t(12;17)(p13;p12-p13), occurring in a patient with an acute myeloid leukemia evolving from a chronic myelomonocytic leukemia. Cytogenetic analysis suggested the presence of a deletion of the short arm of chromosome 12, del(12)(p13), in three of the five metaphase cells analyzed. However, fluorescence in situ hybridization (FISH) with the ETV6-specific cosmid clones 179A6, 50F4, 163E7, and 148B6 as well as probes hybridizing to the TP53 gene on 17p13 and the subtelomeric region of 17p revealed the presence of a translocation between 12p and 17p. By FISH, the breakpoints could be localized in intron 1 of ETV6 and centromeric to TP53. By 3' rapid amplification of cDNA ends-polymerase chain reaction (3' RACE-PCR), a fusion transcript between exon 1 of ETV6 and the antisense strand of PER1 (period homolog 1, Drosophila), a circadian clock gene, could be identified. This ETV6-PER1 (antisense PER1 strand) fusion transcript does not produce a fusion protein, and no other fusion transcripts could be detected. We hypothesize that in the absence of a fusion protein, the inactivation of PER1 or deregulation of a gene in the neighborhood of PER1 may contribute to the pathogenesis of leukemias with a t(12;17)(p13;p12-p13).
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PMID:A novel cryptic translocation t(12;17)(p13;p12-p13) in a secondary acute myeloid leukemia results in a fusion of the ETV6 gene and the antisense strand of the PER1 gene. 1266 Oct 8

In about 55% of acute myeloid leukemia (AML) cases, chromosome aberrations are detectable by cytogenetics. Close correlations between cytomorphology and cytogenetics have been reported. To determine a pattern of cytogenetic abnormalities within the French-American-British (FAB) subtypes AML M0, M1, and M2, we analyzed 48 AML M0, 179 AML M1, and 425 AML M2 and compared cytogenetic data to a cohort of 1,062 AML M3/3v, M4, M4eo, M5a/5b, M6, and M7. Cytogenetic abnormalities were significantly more frequent in AML M0 (71%) compared to M1 (49%), M2 (53%), and the total cohort (56%; P < 0.02). While +8 was the most common numeric abnormality in all FAB subtypes, +13, +14, and +11 were associated with AML M0-M2. The only recurring balanced translocation that was associated with one of these FAB subtypes was t(8;21) in M2 (12.5%) and, rarely, M1 (1.7%) (M0, 0% and M3-7, 0.09%; P=0.001). To evaluate the frequency of cytogenetically undetectable abnormalities, we performed fluorescence in situ hybridization (FISH) analyses in 273 AML M0-M2 with normal karyotype using probes for ETO, ABL, MLL, TEL, RB, P53, AML1, and BCR. In two cases we identified numerical aberrations of RB only in interphases nuclei. In seven additional cases, TEL and MLL abnormalities were found. In conclusion, t(8;21), +11, +13, and +14 are strongly associated with AML M0, M1, and M2. The FISH screening analyses identified abnormalities in an additional 3% in normal karyotypes.
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PMID:Cytogenetic profile in de novo acute myeloid leukemia with FAB subtypes M0, M1, and M2: a study based on 652 cases analyzed with morphology, cytogenetics, and fluorescence in situ hybridization. 1552 2


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