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)

Clonal cytogenetic abnormalities found in 30 non-small cell lung carcinomas (NSCLC), including 28 newly diagnosed primary tumor specimens, are summarized. Multiple chromosome alterations were identified in every case, and 19 of 30 tumors had near-triploid or near-tetraploid karyotypes. Polysomy 7 and partial gains of 7p, including 7p11-p13 (site of the EGFR gene), were particularly frequent, occurring alone or in combination in 26 tumors. Recurrent losses involving 1p, 3p, 6q, 9p, 11p, 15p, and 17p (where the TP53 gene is located) were each seen in 16-25 cases. Five tumors exhibited double minutes, which were associated with amplified MYC1 (1 case) and EGFR (1 case), as determined by Southern analysis. The cytogenetic data were compiled from either short term cultures of tumor tissue harvested within 1-9 days (18 cases) or later harvests performed on long term cultures or cell lines (6 cases); in the other 6 cases results were obtained from both short term and long term cultures. Two studies were performed to validate the use of long term culture for cytogenetic analysis of solid lung tumors. First, in order to determine whether cytogenetic results from cultures are representative of the original tumor, the modal chromosome number of 13 specimens placed into culture was compared to the DNA index of the original tumor tissue, as measured by flow cytometry. The DNA indices of the solid tumor biopsies agreed with the degree of aneuploidy observed by cytogenetic analysis in every case. Second, in 6 cases we performed direct comparisons of karyotypes obtained from cells cultured by both methods. Identical chromosome abnormalities were detected in short term cultures and later harvests of the same specimen. Overall, our findings indicate that tumorigenesis in NSCLC is characterized by the accumulation of multiple chromosome alterations. Furthermore, these data demonstrate that recurrent cytogenetic changes can be identified in NSCLC and that detailed karyotypes from long term cultures are relevant to the original tumor. Chromosome abnormalities detected by these techniques may have clinical and biological significance. However, the complex pattern of karyotypic changes seen in newly diagnosed NSCLC emphasizes the need for future investigations of premalignant bronchial lesions in order to identify primary genetic changes important for early detection and intervention in this aggressive neoplasm.
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PMID:Chromosome abnormalities in human non-small cell lung cancer. 131 34

The frequent occurrence of TF gene involvement in translocations associated with leukemia is remarkable, although not yet explained. The wide variety of TFs involved in these translocations and the different stages of cellular maturation argue against a unifying mechanism. Recombinases, active during B-cell and T-cell development, have been implicated in gene arrangements involving TCR genes and in the SIL/SCL rearrangement, which involves two genes not normally rearranged. However, other mechanisms must clearly be active in generating these molecular abnormalities and perhaps they relate to the multistep maturation and differentiation processes and continuous cell turnover seen in hematopoietic cells. The difficulties in obtaining human solid tumor samples may make it more difficult to identify translocations involving TF genes in solid tumors. Recently, the cytogenetic analysis of solid tumors has improved and specific cytogenetic abnormalities have been associated with specific types of tumors. With advanced techniques, such as fluorescent in situ hybridization (a technique that does not depend on cell growth) and PCR, abnormalities involving TF genes will be discovered. Abnormalities of TF genes, other than translocations, have been seen in a broad variety of nonhematopoietic malignancies. The p53 protein has been shown to bind DNA in a sequence-specific fashion and interact with a variety of DNA tumor virus oncoproteins. The broad range of cell types that harbor p53 abnormalities suggests that TF abnormalities will likely be implicated in many solid tumors. We have detailed several examples of how gene rearrangements that accompany chromosomal translocations in acute leukemia can alter the expression or activity of cellular TFs. Several translocations generate fusion RNA transcripts and fusion TF proteins with altered functional characteristics. Other translocations result in the expression of a gene not normally detectable in hematopoietic cells or alter the level of its expression, or affect the promoter usage or exon structure of the gene (Table 2). Studies are underway in many laboratories to characterize the biologic activity of these abnormal TFs and it remains to be proven that these molecular abnormalities are directly linked with leukemogenesis. The identification of abnormal fusion transcripts and proteins may allow specific therapies to be directed against "tumor-specific" DNA, mRNA, or protein targets. Therapeutic strategies based on antisense or ribozyme technology may be used to turn off expression of these genes and inhibit leukemia cell growth. Immunologic methods can also be used to direct therapy against the malignant cells.
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PMID:Transcription factors, translocations, and leukemia. 136 70

The BCL2 gene product has been demonstrated to prevent apoptosis and provide a selective growth advantage to many cell types. We report an unexpected effect of bcl2 expression on the in vitro growth of several solid tumor cell lines. Expression of bcl2 in these cell lines resulted in growth inhibition similar to that seen with p53. In contrast, a COOH-terminal deletion mutant of bcl2 was unable to suppress growth. Thus, the bcl2 protein may exert distinct biological effects in different cell types.
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PMID:Paradoxical inhibition of solid tumor cell growth by bcl2. 803 89

Mutations of the p53 tumor suppressor gene occur frequently in a variety of adult-onset tumors, including colon, breast, lung, and brain, yet are infrequently identified in pediatric malignancies. Wilms' tumor, a common solid tumor of childhood, can be associated with mutations of the WT1 gene. Alterations of the p53 gene have been shown to modulate the ability of WT1 to transactivate its targets. Although positive p53 immunostaining has been demonstrated in Wilms' tumors, the correlation to p53 gene mutations is not clear. We examined Wilms' tumor samples for p53 mutations utilizing polymerase chain reaction-single-strand conformation polymorphism analysis and single-strand DNA sequencing. Mutations in the coding region of the p53 gene were demonstrated in 2 of 21 (9.5%) Wilms' tumors. Each mutation yielded a substitution of amino acid residues. One mutation was located in exon 6 and the other in exon 7. Both mutations were found in tumors from patients with advanced stage disease. Focal anaplasia was demonstrated in one of these tumors. Our data suggest that although p53 mutations occur infrequently in Wilms' tumor, they may be associated with advanced disease.
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PMID:Mutations of the p53 tumor suppressor gene occur infrequently in Wilms' tumor. 817 7

In a mouse model of multistage tumorigenesis of islet beta-cells, apoptosis was activated concomitant with T-antigen oncogene-induced cell proliferation, further increased in the angiogenic stage, and markedly reduced in solid tumors. Crosses to p53-null mice confirmed this stage-specific variation as a p53-independent apoptotic process. Several apoptosis regulators were expressed, of which bcl-xL was up-regulated in tumors. When overexpressed throughout the pathway, bcl-xL protected most oncogene-expressing cells from apoptosis, enhancing progression from angiogenic progenitor to tumor without affecting earlier transitions. Further, two classes of solid tumor are described, distinguished by size and apoptotic incidence, implicating apoptosis regulation in expansive tumor growth. Thus, down-modulation of apoptosis selectively contributes to late steps in a tumorigenesis pathway.
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PMID:The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. 880 6

We performed a mutational analysis of the p53 gene in matched samples of solid tumors and ascites from patients with ovarian cancer using the single-strand conformation polymorphism technique on exons 5-9 of the p53 gene on fresh and cultured material. We observed a discordance in the pattern of p53 mutations between the ascites and their solid tumor counterpart. In two cases, cancer cells from ascites carried a p53 mutation and the corresponding solid tumor cells retained the wild-type allele, while the opposite pattern was observed in two other patients samples. These results suggest that ovarian tumor cells within the ascites may not simply represent cells shed from the ovarian solid tumor and bear directly on gene therapy strategies in ovarian cancer.
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PMID:Discordance in p53 mutations when comparing ascites and solid tumors from patients with serous ovarian cancer. 914 13

A new cell line designated CUME-1 has been established from a poorly differentiated endometrial adenocarcinoma of the uterus. This cell line grew well without interruption for more than 88 months and 110 serial passages were successively carried out. The cells were highly tumorigenic in nude mice (85%). Repeated karyotype analyses from early (4th) to late (55th) passages of this cell line revealed a diploid stable clone in each passages without any noticeable structural or numerical aberrations. But from the 80th passage, a subpopulation with reciprocal translocation between chromosomes 1q and 9q consistently appeared and was observed in about 30% of the cells. This cell line is one of the rare examples of experimentally proved tumorigenic cells of human solid tumor origin that retains the diploid karyotype in vitro. HLA typing indicated the presence of DR4, DR13, DQ3 and DQ6. Cytosol estrogen and progesterone receptors were found both in fresh primary tumor and in this cell line. Gonadotropin-releasing hormone (Gn-RH) receptor mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) in cultured cells. Using the single-strand conformation polymorphism (SSCP) technique, we have screened CUME-1 cells for p53 mutation in exons 4 to 9. No mobility shift was observed. This cell line may be useful in studying the in vitro chromosomal evolution of the cell line and the in vivo properties of human endometrial adenocarcinoma.
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PMID:Establishment and characterization of a highly tumorigenic human diploid endometrial cancer cell line. 935 88

Cellular checkpoints are important mediators of the response of normal cells following genotoxic damage, and interruption of these checkpoints is a common feature of many solid tumors. Although the effects of loss in checkpoint function in tumor cells are well understood in terms of cell cycle control, there is little information on their role in determining treatment efficacy in vivo. We have examined both the in vitro and in vivo responses of isogenic lines differing only in the p53-transactivated checkpoint gene, p21Waf1/Cip1. When assayed in vitro, loss of p21 in human colon tumor cells results in a selective induction of apoptosis [Waldman, T., et al., Nature (Lond.), 381: 713-716, 1996.] but no difference in the clonogenic survival. However, when grown as xenografts and irradiated in situ, p21-deficient tumors were significantly more sensitive to radiation as assessed both by clonogenic survival and by regrowth of the tumors following treatment. These data indicate that loss of p21 results in increased sensitivity to killing by ionizing radiation that is independent of the induction of apoptosis and cell cycle arrest but that is specific to cells when they are grown as a solid tumor. These results have important implications for assessing both the genetic determinants of sensitivity to anticancer agents and efficacy of anticancer agents.
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PMID:Loss of p21Waf1/Cip1 sensitizes tumors to radiation by an apoptosis-independent mechanism. 935 25

The basic helix-loop-helix protein MyoD induces muscle structural gene expression and cell cycle withdrawal in many nontransformed cell lines. We show that MyoD activation of transcription of the cyclin-dependent kinase inhibitor p21 does not require synthesis of an intermediary protein. In most of the rhabdomyosarcoma and other solid tumor cell lines that we analyzed, p21 levels were abnormally low and correlated with the combined inactivity of MyoD and p53, two known transcriptional activators of p21. Loss of MyoD activation of p21 transcription correlated with the failure to arrest in G1, and expression of p21 caused accumulation of cells in G1, further supporting a role for p21 in MyoD-induced cell cycle arrest. Finally, different tumor types have inactivated distinct factors necessary for p21 expression, because p21 expression was reconstituted in hybrid cell lines. We propose that p21 integrates growth-inhibitory signals from independent p53 and basic helix-loop-helix pathways, and that in the majority of tumor cell lines, both pathways are abrogated.
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PMID:Inactivation of MyoD-mediated expression of p21 in tumor cell lines. 937 38

A decrease in the intracellular concentrations of the transcripts for some tumor suppressor genes has been found during murine lung tumorigenesis; for p15INK4b and p16INK4a, this was due to homozygous deletions. We report here a decrease in the mRNA levels of the mutated in colorectal cancer (Mcc) and adenomatous polyposis coli (Apc) genes in mouse lung tumors and some neoplastic cell lines. This was assessed both by northern blotting and reverse transcriptase-polymerase chain reaction of RNA isolated from lung tumors that had been induced by urethane, N-nitrosodiethylamine, or 3-methylcholanthrene in (A/J x C57BL/6) F1 or A/J mice. A reduced amount of both Mcc and Apc messages was also seen when two neoplastic cell lines, a spontaneous transformant (E9) and a line derived from a chemically induced solid tumor (82-132), were compared with two independently derived nontumorigenic cell lines (E10 and C10); E9 was derived from E10, and all of these lines are probably of alveolar type 2 cell origin. A cell line derived from a chemically induced papillary lung tumor probably of bronchiolar Clara cell origin (LM2) had Mcc mRNA levels similar to those of C10 and E10 but reduced Apc mRNA levels. A line (p53-823) derived from a papillary tumor that arose in a mouse with a mutated p53 transgene had a reduced amount of the Mcc gene product only. These differential changes in the relative amounts of Apc and Mcc messages in LM2 and p53-823) cells may serve as useful models for studying the regulation of their expression. Both messages had half-lives of 6-9 h in normal E10 and neoplastic E9 cells, so decreased message stability does not account for these reductions. This is the first report of estimated degradation rates of these mRNAs. Apc and Mcc message content did not vary as a function of growth status of the cell lines. Single-strand conformation polymorphism analysis did not reveal mutations in Apc coding regions known to have a high mutation frequency in human colon tumors. Loss of heterozygosity of Apc and Mcc was not found in tumors that developed in the F1 mice, implying a lack of allelic deletions. These changes in tumor suppressor gene expression may contribute to the development and maintenance of neoplasia in lung epithelium.
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PMID:Decreased expression of the adenomatous polyposis coli (Apc) and mutated in colorectal cancer (Mcc) genes in mouse lung neoplasia. 947 70


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