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)

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

Deranged expression of cell cycle modulators has been reported to contribute to the development and progression of hepatocellular carcinoma (HCC). However, their expression patterns remain poorly understood in hepatitis B virus (HBV)-related HCC, which constitutes about 65-70% of HCC in Korea. The aims of this study were to evaluate the expressions of G1-S modulators in HBV-related HCCs and dysplastic nodules (DNs), and to correlate with the histopathologic features of HCCs. Immunohistochemical expressions of cyclin D1, cyclin E, p53, p27, p21, p16, Rb, and PCNA proteins were investigated in 80 HCCs and 22 DNs. Cyclin D1 overexpression showed positive relationships with advanced tumor stage, poor differentiation, larger tumor size, microvascular invasion, intrahepatic meta-stasis, no tumor capsule formation, infiltrative growth, aberrant p53 expression, and high PCNA labeling index (LI) of HCC (p<0.05). Aberrant p53 expression showed positive relationship with poor differentiation of HCC (p<0.01). Expression of cyclin D1 or p53 was not observed in DNs. The p27 LI and p16 LI were lower in HCCs with intrahepatic metastasis (p<0.05). Cyclin D1 overexpression and aberrant p53 expression could be associated with the progression of HBV-related HCC, and might have a less crucial role in the DN-HCC sequence. In addition, elevated expression of p27 and p16 proteins might have inhibitory action to the intrahepatic metastasis of HBV-related HCC.
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PMID:Expression of the G1-S modulators in hepatitis B virus-related hepatocellular carcinoma and dysplastic nodule: association of cyclin D1 and p53 proteins with the progression of hepatocellular carcinoma. 1151 87

The immortalization of human cells is a critical step in multistep carcinogenesis. Oral-esophageal carcinomas, a model system to investigate molecular mechanisms underlying squamous carcinogenesis, frequently involve cyclin D1 overexpression and inactivation of the p53 tumor suppressor. Therefore, our goal was to establish the functional role of cyclin D1 overexpression and p53 inactivation in the immortalization of primary human oral squamous epithelial cells (keratinocytes) as an important step toward malignant transformation. Cyclin D1 overexpression alone was found to induce extension of the replicative life span of normal oral keratinocytes, whereas the combination of cyclin D1 overexpression and p53 inactivation led to their immortalization. This study also demonstrates that immortalization of oral keratinocytes can be independent of telomerase activation, involving an alternative pathway of telomere maintenance (ALT).
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PMID:Cyclin D1 overexpression and p53 inactivation immortalize primary oral keratinocytes by a telomerase-independent mechanism. 1154 71

Prognosis of lung cancer is related to stage of disease at time of diagnosis. In this study we examine alterations of pathways governing the cell cycle, in particular pRb-cyclinD1-p16 alpha and p53-p14ARF, in a series of NSCLC (n=92) at different stages at diagnosis. Using immunohistochemistry, we assessed the expression of the retinoblastoma protein (pRb), cyclin D1, p16 alpha, p53 and p14ARF. Tumours in stage I-IIIA (resectable) were more likely to have alterations in the pRb-cyclinD1-p16 alpha pathway than tumours in advanced stage (IIIB-IV) (90% versus 63%, P=0.002). pRb and p14ARF were more frequently downregulated in resectable tumours (P< or =0.03), and cyclin D1, p16 alpha, and p53 were altered at a similar frequency in resectable and advanced tumours. In 12 patients, metastatic sites (5 lymph node, 3 bone, 2 brain and 2 gastrointestinal metastases) were available for comparison with the primary tumour: 19 altered protein expressions were found to be concordant, six additional alterations (in 4 patients) were found in the metastases only, especially in lymph node metastases (3 patients). Compared with normal protein expression, both pathway alterations were associated with a longer survival (P=0.02). In a multivariate analysis (Cox regression) this difference was not maintained after adjustment for age, stage and tumour differentiation. Cyclin D1 was the sole protein with independent prognostic value in resectable tumours: the relative risk of local relapse was 4.7 in tumours without cyclin D1 overexpression (P=0.02, Cox regression analysis). No protein studied had a predictive significance for response after chemotherapy in non-resectable tumours. These results demonstrate a strong correlation between stage and pathway alterations, cell cycle regulators being less likely altered in advanced NSCLC. Tumours with defects in these control pathways tend therefore to remain localised and to metastasize at a later phase in tumour development. This finding might be an explanation for distinct biological behaviour (e.g. chemotherapy response) of resectable versus advanced disease.
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PMID:Alterations of cell cycle regulators are less frequent in advanced non-small cell lung cancer than in resectable tumours. 1155 18

The immunohistochemical expression of p53, p21, Rb, p16, cyclin D1, Ki67, cyclin A, cyclin B1, p27, bcl2, bax, and bak proteins and the apoptotic index (Al) were investigated in 20 normal thymuses (8 adults, 3 adolescents, 5 infants and 4 newborns). The expressions of Rb, Ki67, cyclin A and cyclin B1 were overlapping, being high in the cortex with a tendency for decreased expression toward the medulla. Apoptotic cells were mainly detected in the cortex and the corticomedullary junction, rarely being present in Hassall's corpuscles. The mean values of Ki67, cyclin A, and cyclin B1 expression in thymuses were 77.2%, 32.2% and 21.4% (newborns), 62.4%, 33.7% and 18.5% (infants), 56.9%, 23.4% and 18.9% (adolescents) and 38.7%, 21.7% and 14.6% (adults), respectively. The mean values of AI in thymuses from newborns, infants, adolescents and adults were 1.4%, 2.9%, 2.7% and 3.8%, respectively. This decrease in proliferation and increase in apoptosis may account for the process of thymic involution. P16 expression was widespread with most of Hassall's corpuscles being p16-positive. P16-positive cells and Hassall's corpuscles increased with the increase in age, in keeping with the suggested role of p16 in cellular senescence. P27 expression was undetectable in subcapsular thymocytes with a tendency for increased expression toward the medulla. The expressions of Ki67, cyclin A and cyclin B1 were inversly related with that of p27, consistent with previous evidence that p27 concentration is reduced when the cell-cycle progresses. P21 and much less frequently p53 proteins were mainly detected in a part of the subcapsular cortical epithelial cells. These findings suggest that a) in thymocytes, the apoptotic pathway is mostly p53-independent and the function of p21 as a negative regulator of the cell cycle must be redundant to other negative regulators, such as p16 and p27 which were abundantly detected in thymocytes and b) in some thymic epithelial cells, the p21 expression may be induced by p53, but in most of them seems to be p53-independent. Most of Hassall's corpuscles were p21-positive, consistent with previous evidence that these structures represent end stages of maturation of thymic medullary epithelium and that p21 protein is involved in the process of terminal differentiation. Cyclin D1 positivity was found in some macrophages. Bcl2 expression was mainly seen in medullary thymocytes, reflecting the surviving thymocytes in this region. The expressions of Bax and bak were more widespread in both the medulla and cortex, suggesting that these proteins play a broader role than bcl2 in the regulation of thymic apoptosis.
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PMID:Immunohistochemical expression of p53, p21/waf1, rb, p16, cyclin D1, p27, Ki67, cyclin A, cyclin B1, bcl2, bax and bak proteins and apoptotic index in normal thymus. 1164 19

The differentiation of neuronal cells in the developing mammalian retina is closely coupled to cell cycle arrest and proceeds in a highly organized manner. Cyclin D1, which regulates cell proliferation in many cells, also drives the proliferation of photoreceptor progenitors. In the mouse retina, cyclin D1 protein normally decreases as photoreceptors mature. To study the importance of the down-regulation of cyclin D1 during photoreceptor development, we generated a transgenic mouse in which cyclin D1 was persistently expressed in developing photoreceptor cells. We observed numerous abnormalities in both photoreceptors and other nonphotoreceptor cells in the retina of these transgenic mice. In particular, we observed delayed opsin expression in developing photoreceptors and alterations in their number and morphology in the mature retina. These alterations were accompanied by disorganization of the inner nuclear and plexiform layers. The expression of cyclin D1 caused excess photoreceptor cell proliferation and apoptosis. Loss of the p53 tumor suppressor gene decreased cyclin D1-induced apoptosis and led to microscopic hyperplasia in the retina. These findings are distinct from other mouse models in which the retinoblastoma gene pathway is disrupted and suggest that the IRBP-cyclin D1 mouse model may recapitulate an early step in the development of retinoblastoma.
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PMID:Persistent expression of cyclin D1 disrupts normal photoreceptor differentiation and retina development. 1170 9

Germline mutations in the tumor suppressor gene BRCA1 predispose women to breast cancer, however somatic mutations in the gene are rarely detected in sporadic cancers. To understand this phenomenon, we examined mouse models carrying conditional disruption of Brca1 in mammary epithelium in either p53 wild type (wt) or heterozygous backgrounds. Although a p53(+/-) mutation significantly accelerated tumorigenesis, both strains developed mammary tumors in a stochastic fashion, suggesting that multiple factors, in addition to p53 mutations, may be involved in Brca1 related tumorigenesis. A unique feature of Brca1 mammary tumors is their highly diverse histopathology accompanied by severe chromosome abnormalities. The tumors also display extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27 and Cyclin D1 in the majority of tumors, while they were virtually ERalpha and p16 negative. Translocations involving p53 were also identified which lead to abnormal RNA and protein products. In addition, we generated cell lines from mammary tumors and found that the cells retained many of the genetic changes found in the primary tumors, suggesting that these genes may be players in Brca1-associated tumorigenesis. Despite their distinct morphology, all cultured tumor cells were Tamoxifen resistant but highly sensitive to Doxorubicin or gamma-irradiation, suggesting that these methods would be effective in treatment of this disease.
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PMID:Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. 1170 23

Pancreatic cancer (PC) is thought to develop through a series of duct lesions termed pancreatic intraepithelial neoplasia (PanIN). Characterization of the molecular pathology of these lesions may lead to additional understanding of pancreatic ductal carcinogenesis. We examined the protein expression of four functionally related genes, p21(WAF1/CIP1) (CDKN1A), p53, cyclin D1 (CCND1), and DPC4/Smad4 (MADH4), aberrations of which are associated with PC, within 451 PanIN lesions present in the pancreata of 60 patients. p21(WAF1/CIP1) overexpression was present in the normal ducts of 9% of patients and increased progressively to 16% of patients with PanIN-1A lesions, to 32% of patients with PanIN-1B lesions, 56% of patients with PanIN-2 lesions, 80% of patients with PanIN-3 lesions, and 85% of patients with invasive carcinomas (P < 0.01). p53 and cyclin D1 overexpression occurred predominantly in PanIN-3 lesions (P < 0.01), and loss of DPC4/Smad4 expression occurred predominantly in PanIN-3 lesions and invasive carcinoma (P < 0.01). In addition, p21(WAF1/CIP1) overexpression occurred independently of p53 and DPC4/Smad4 expression within invasive carcinoma and PanIN-3 lesions. Cyclin D1 overexpression or loss of DPC4/Smad4 expression was apparent in 85% of invasive carcinomas but in only 14% of PanIN-2 lesions. These data demonstrate that overexpression of p21(WAF1/CIP1) occurs early in the development of PanIN, before aberrations in p53, cyclin D1, and DPC4/Smad4 expression. p21(WAF1/CIP1) overexpression, independent of p53 and/or DPC4/Smad4 expression, may reflect increased Ras activity, either directly through activating K-ras mutations or as a consequence of HER-2/neu (ERBB2) overexpression, both of which are common in PC and in early events in the development of PanIN. These data support further the current progression model for PC and demonstrate that aberrant expression of key cell cycle regulatory genes may be important in the early development and progression of PanIN.
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PMID:Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. 1175 5

Uwhangchungsimwon (pill, UC) is one of the traditional Korean medical prescriptions that has been most frequently used for stroke. To characterize the effects of UC on human neuronal cells, the human neuroblastoma cell line IMR32 was treated with UC, and cell viability, cell proliferation, apoptosis, and gene expression were analyzed. The effect of UC on recovery of cell viability was analyzed following stress induction by nutrient depletion or cold shock. Flow cytometric analysis of the cell cycle showed that UC inhibits cell cycle progression of IMR32 in a dose- and time-dependent manner. UC was also identified to increase cell viability and suppress apoptosis induction by a DNA-damaging agent, etoposide. Quantitative RT-PCR analysis revealed that expressions of the p53 tumor suppressor gene and its downstream effect, Waf1, are stimulated whereas expressions of positive cell cycle regulators, c-Myc, c-Fos, and Cyclin D1 were repressed by UC treatment. Moreover, while expression levels of apoptosis inhibitors, Bcl-2 and Bcl-XL were increased following UC treatment, that of an apoptosis promoter, Bax, was decreased. In addition, expression of BMP-7, which has been recently demonstrated to improve the motor neuron recovery from stroke, was induced by UC while it was not detected in untreated cells. Taken together, our data suggest that the pharmacoclinical effects of UC might be derived in part from its negative regulation of cell proliferation and apoptosis through the transcriptional control of related genes.
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PMID:Effects of uwhangchungsimwon on cell viability, proliferation, and gene expression of human neuronal cell line IMR32. 1178 87

The tumor suppressor p53 gene product is an essential component of the cytotoxic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We previously demonstrated that adenovirus-mediated wild-type p53 gene transfer could enhance the cytotoxic actions of chemotherapeutic drugs both in vitro and in vivo; however, the molecular mechanism of this chemosensitization is still unclear. Cyclin D1 is a major regulator of the progression of cells into the proliferative stage of the cell cycle. Here we show that infection with an adenovirus vector expressing the wild-type p53 gene (Ad-p53) caused an increase in cyclin D1 protein levels in human colorectal cancer cell lines DLD-1 and SW620; treatment with the anti-cancer drug adriamycin, however, down-regulated their cyclin D1 protein expression in a dose-dependent manner. The suppression of cyclin D1 expression following adriamycin treatment could be blocked by simultaneous Ad-p53 infection. Furthermore, DLD-1 and SW620 cells transfected with the cyclin D1 expression construct displayed increased sensitivity to adriamycin compared to that of the vector-transfected control. Our results suggest that ectopic wild-type p53 gene transfer results in increased cyclin D1 expression and, consequently, sensitizes human colorectal cancer cells to chemotherapeutic agents.
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PMID:p53 inhibits adriamycin-induced down-regulation of cyclin D1 expression in human cancer cells. 1179 89


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