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)

Acquired drug resistance of tumor cells is frequently observed in cancer patients undergoing chemotherapy. We studied murine leukemia L1210 cells sensitive and resistant to the cytotoxic action of cisplatin and showed that cisplatin-resistant leukemia cells were also refractory to TGF beta1-dependent growth inhibition and apoptosis. Addressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF beta1, we found that cisplatin- and TGF beta1-resistant L1210 cells possessed a decreased expression of type I TGF beta1 receptor, while the expression of type II TGF beta1 receptor was not affected. Western blot analysis of Smad proteins 2, 3, 4, 6, and 7, which participate in signal transduction pathway down-stream of the TGF beta1 receptors, revealed an increased expression of Smad 6, inhibiting TGF beta1 action, only in cisplatin- and TGF beta1-resistant L1210 cells. TGF beta1 and especially the cytotoxic mistletoe agglutinin increased Smad 6 expression in TGF beta1-sensitive but not in TGF beta1-resistant L1210 cells. TGF beta1-resistant L1210 cells also differed from TGF beta1-sensitive cells by the lack of expression of the pro-apoptotic p53 protein and higher level of expression of the anti-apoptotic Bcl-2 protein. Thus, the described co-expression of tumor cell refractoriness to an anti-cancer drug and to the inhibitory cytokine TGF beta1 is accompanied by multiple changes in the TGF beta1 signal transduction pathway and in other regulatory systems of the target cells. Besides, we found that various anti-tumor drugs and cytotoxic plant lectins increased the level of TGF beta1 expression in both TGFbeta1-sensitive and -resistant L1210 cells. A hypothesis is proposed that TGFbeta1 can at least partly mediate the effect of cell-stressing agents and, thus, the development of TGF beta1 resistance may be responsible for the appearance of tumor cell refractoriness to the action of some anti-cancer drugs.
Acta Biochim Pol 2003
PMID:Potential role of transforming growth factor beta1 in drug resistance of tumor cells. 1283 74

Butyric acid, a short chain fatty-acid derived from bacterial fermentation of complex carbohydrates in the large intestine has been shown to be a growth inhibitory in many colon cancer cell lines. Butyrate induced inhibition of cellular proliferation is considered to result from the induction of P21 gene expression through the activation of this gene transcription. P21 is an inhibitor of cyclin-dependent protein kinases that are required for the cells to enter the DNA synthesis phase. In the present study the kinetics of the changes of the P21 transcription in Caco-2 colon adenocarcinoma cells treated with various concentrations of sodium butyrate was determined using a novel real-time quantitative RT-PCR (TaqMan) technique. Beta-actin mRNA and GAPDH mRNA levels were used as the endogenous references. Colonocytes were incubated with sodium butyrate at concentrations of 5 mM, 10 mM and 20 mM for 3, 6, 12, 24 and 48 h. The results of this study indicated that butyrate strongly induced P21 gene expression as early as 3 h after treatment. Characteristic patterns of time-dependent changes of the target gene expression were observed. The increases in P21 mRNA level were generally more pronounced at higher butyrate concentrations. Because Caco-2 cells are lacking the wild allele of the P53 gene, the present results support the hypothesis that butyrate induces P21 gene expression by P53-independent mechanism.
Acta Pol Pharm
PMID:Quantification of p21 gene expression in Caco-2 cells treated with sodium butyrate using real-time reverse transcription-PCR (RT-PCR) assay. 1367 14

Tumour growth and its progression to a metastatic phenotype involves a serious of genetic events with abnormal activation of oncogenes or inactivation of tumour suppressor genes and others genes connected with proliferation, apoptosis and neovascularisation. The aims of the study were to determine the possible prognostic value of angiogenesis, proliferation index Ki67, p53 and bcl-2 proteins expression in patients with laryngeal cancer. The group of 151 patients with laryngeal cancer, surgically treated with minimum 5 years observation, was multi-variously analysed. Paraffin--embedded tissue sections from each case were stained with a monoclonal antibody raised against FVIII antigen, p53 and bcl-2 proteins and Ki67 proliferation antigen using a peroxidase labelled streptavidin--biotin kit in standard immunohistochemistry techniques. In univariate analysis: staging IV, tumour size T4, nodal metastasis N2 and N3, local and nodal recurrences, high expression of Ki67 and P53, high (over median) IA measured as number of microvessels with FVIII expression were significantly associated with shortened overall survival. Disease-free survival was related to: proliferation index Ki67, expression of P53 protein and angiogenesis measured as microvessels density with expression of FVIII antigen. In multivariate analysis the most important death risk factors for overall survival were: tumour size, nodal metastasis, local and nodal recurrences, P53 protein expression and IA measured as number of microvessels with FVIII expression. In multivariate analysis of disease-free survival only P53 protein expression, proliferative index Ki67 and expression of FVIII had independent prognostic value. Intensity of angiogenesis, proliferation index of Ki67 antigen and expression of P53 protein were independent predictors of patients with laryngeal cancer outcome. In contrary Bcl2 protein seems to be useless in these patients.
Otolaryngol Pol 2003
PMID:[Survival of patients with laryngeal cancer and some prognostic factors]. 1452 74

Apoptosis is a physiological process of cell death by which a single cell may be eliminated from the living tissue. Since the process is mediated by specific proteins encoded in the host's genome, it is also a programmed cell death. Apoptosis is responsible for tissue remodelling during the development and turnover of normal tissue (e.g. haematopoietic cells) throughout the life span of multicellular organisms. In contrast to cells undergoing a pathological cell death (necrosis), the morphological changes that accompany apoptosis are characterised by condensation of chromatin and cytoplasm and subsequent fragmentation of the cell into small membrane-bound segments called apoptotic bodies. The maintenance of membrane integrity in apoptosis prevents the release of deleterious cytoplasmic substances and the activation of inflammatory responses. Apoptosis can be initiated by a variety of events arising either within the cell (p53) or externally (death receptor ligands engaging specific cell surface receptors of the target cell). Following recognition of the stimuli and clustering of membrane proteins into a death domain, certain cytoplasmic proenzymes are converted to their active form (caspases). After the death effector machinery is activated, the cell enters the irreversible common degradation phase of cytoskeletal disorganisation. Survival proteins (bcl-2 family) control the caspase-driven engine of destruction. Disordered apoptotic process participates in the pathogenesis of various diseases, such as neoplasms, chronic inflammatory or systemic autoimmune diseases, and other conditions.
Neurol Neurochir Pol
PMID:[Apoptosis: physiological cell death and its role in pathogenesis of diseases]. 1455 80

Cyclin-dependent kinases (CDKs) have recently raised considerable interest in view of their key role in the regulation of the cell cycle progression. In proliferating cells, distinct CDKs associated with specific cyclins coordinate in an orchestrated way the appropriate transition between different phases of the cell cycle. Mutations and/or aberrant expression of distinct CDKs and their regulatory components lead to uncontrolled proliferation and finally to carcinogenesis. However, in post-mitotic neurons, all CDKs with the exception of CDK5 are silent. CDK5, a proline-directed serine/threonine kinase exhibiting a close structural homology to the mitotic CDKs, binds to p35, the neuron-specific regulatory subunit of CDK5. CDK5 is very abundant in mature neurons and seems to regulate neurotransmitter release through phosphorylation and down-regulation of calcium channel activity. Therefore, the inhibition of CDKs in neurons after oxidative stress and in neurodegenerative disorders has a protective action. Selective CDKs inhibitors were developed as promising drugs for cancer therapy due to their ability to arrest cell cycle progression. The aim of this study was to compare the anti-proliferative effect of roscovitine (ROSC), a potent CDKs inhibitor, with that of cisplatin (CP) on human breast cancer MCF-7 cells. ROSC exerted stronger inhibitory effect on proliferation and cell cycle progression of MCF-7 than CP. Accumulation of G(2)/M arrested cells starting 6 h after onset of ROSC treatment coincided with a strong up-regulation of the p53. Reconstitution with caspase-3 sensitized MCF-7 cells to CP action. It implicates that ROSC inhibits more selectively and efficaciously the proliferation of human breast carcinoma cells.
Pol J Pharmacol
PMID:Dual action of cyclin-dependent kinase inhibitors: induction of cell cycle arrest and apoptosis. A comparison of the effects exerted by roscovitine and cisplatin. 1470 84

CD44-protein and its isoforms are the multifunctional cell adhesion molecules participating in cell-cell and cell-matrix interactions. In this study we estimated the frequency of CD44-expression as well as two of its variants (CD44v3 and CD44v5) in female breast cancer. Among 75 breast carcinomas studied, 23 (44.2%) presented strong membrane reaction with monoclonal antibody against antigen CD44. The immunocytochemical reaction to CD44v3 and CD44v5 were observed in 16 (21.3%) and 50 (66.75%) cases, respectively. The presence of CD44v3 antigen on the surface of breast cancer cells significantly correlated with ER expression (0.0430) and the lack of p53 protein (p=0.0252), and also with the percentage of T cells in the total population of lymphocytes infiltrating the primary tumor (TILs) (p=0.0248). What is more important, the reaction to CDv3 significantly correlated with the presence of metastases to the lymph nodes (p=0.0385).
Pol J Pathol 2003
PMID:The role of CD44v3 expression in female breast carcinomas. 1499 92

In a group of 75 untreated patients with a typical B cell chronic lymphocytic leukaemia (B-CLL) (CD19+, CD5/CD19+, CD23/CD19+), the frequency and clinical significance of TP53 gene deletion and chromosome 12 trisomy were assessed. The studies of peripheral blood lymphocytes were conducted using interphase in situ hybridization technique. Clonality was identified when TP53 deletion or chromosome 12 trisomy was found in at least 10% of cells. From all 75 examined patients 32 individuals without any of the genetic aberrations were analyzed (Group I) and 30 subjects with TP53 deletion (Group II) were chosen. In the other 13 patients, discussed in the next paper, either chromosome 12 trisomy (Group III--seven subjects) or both chromosome 12 trisomy and TP53 deletion (Group IV--six subjects) were found. In the Group I, there has been no further contact with three patients, while in the Group II--with two individuals. In the Group I, one patient of 29 in the study (3%) died after 84 months (seven years) from the diagnosis, whereas in the Group II--nine subjects of 28 in the study (32%) died within 1-36 months from the diagnosis. In three of those patients in the terminal condition, cytogenetic studies were repeated revealing an increase of approximately 5% in the percentage of peripheral blood cells with TP53 deletion. The frequent presence of TP53 deletion detected in 48% of patients is surprising. It is generally thought that the aberration is found in 10-15% of clinical cases. The studies should be confirmed on a larger group of patients.
Pol Arch Med Wewn 2003 Dec
PMID:[Some genomic aberrations in B-cell chronic lymphocytic leukemia and their clinical relevance. Part I. B-cell lymphocytic leukemia with TP53 gene deletion]. 1505 34

Among 75 untreated patients with typical (CD19+, CD5/CD19+, CD23/CD19+) B-cell chronic lymphocytic leukemia (B-CLL) cytogenetic aberrations of peripheral blood cells were evaluated, using fluorescence in situ hybridization techniques. Two cytogenetic aberrations were evaluated: trisomy 12 and TP53 deletion. The clonality was determined when > or = 10% of the cells had of trisomy 12 or deletion TP53 gene. Trisomy 12 in 7 patients was detected, while trisomy 12 and TP53 deletion simultaneously in 6 patients were present. If the first group will be linked to the second one then 13 patients among 75 (17%) will have trisomy 12. In group of patients with trisomy 12 and TP53 deletion percentage of cells with trisomy 12 was almost two time more compare to patients with trisomy 12 as a single aberration. It is possible, that TP53 deletion ("the guardian of the genome") facilitates proliferation clones with others genomic aberrations. In two patients with trisomy 12 control cytogenetic study was performed. Increase of percentage cells with trisomy 12 for 8% and 30% respectively was detected. However, proliferation of cells with TP53 deletion was observed too. Clinical course of B-CLL in group of patient with trisomy 12, trisomy 12 and TP53 deletion simultaneously is more aggressive compared to the course of disease of patients with no cytogenetic aberrations (patients of Group I from Part I of paper). Frequency of IGHV gain mutation occurrence was not analyzed in both groups of patients. But trisomy 12 together with unmutated IGHV gene is found by some authors. The absence IGHV gene mutation is independent unfavourable prognostic factor.
Pol Arch Med Wewn 2003 Dec
PMID:[Some genomic aberrations in B-cell chronic lymphocytic leukemia and their clinical relevance. Part II. Trisomy 12 in B-cell chronic lymphocytic leukemia detected by fluorescence in situ hybridization]. 1505 38

Retinoic acid and transforming growth factor-beta (TGF-beta) affect differentiation, proliferation and carcinogenesis of epithelial cells. The effect of both compounds on the proliferation of cells of the hormone sensitive human breast cancer cell line (ER+) MCF-7 was assessed in the presence of estradiol and tamoxifen. The assay was based on [3H]thymidine incorporation and the proliferative activity of PCNA- and Ki 67-positive cells. The apoptotic index and expression of the Bcl-2 and p53 antigens in MCF-7 cells were also determined. Exogenous TGF-beta1 added to the cell culture showed antiproliferative activity within the concentration range of 0.003-30 ng/ml. Irrespective of TGF-beta1 concentrations, a marked reduction in the stimulatory action of estradiol (10(-9) and 10(-8) M) was observed whereas in combination with tamoxifen (10(-7) and 10(-6) M) only 30 ng/ml TGF-beta1 caused a statistically significant reduction to approximately 30% of the proliferative cells. In further experiments we examined the effect of exposure of breast cancer cells to retinoids in combination with TGF-beta1. The incorporation of [3H]thymidine into MCF-7 cells was inhibited to 52 +/- 19% (control =100%) by 3 ng/ml TGF-beta1, and this dose was used throughout. It was found that addition of TGF-beta1 and isotretinoin to the culture did not decrease proliferation, while TGF-beta1 and tretinoin at low concentrations (3 x 10(-8) and 3 x 10(-7) M) reduced the percentage of proliferating cells by approximately 30% (67+/-8% and 67+/-5%, P<0.05 compared to values in the tretinoin group). Both retinoids also led to a statistically significant decrease in the stimulatory effect of 10(-9) M estradiol, attenuated by TGF-beta1. In addition, the retinoids in combination with TGF-beta1 and tamoxifen (10(-6) M) caused a further reduction in the percentage of proliferating cells. Immunocytochemical analysis showed that all the examined compounds gave a statistically significant reduction in the percentage of cells with a positive reaction to PCNA and Ki 67 antigen. TGF-beta1, isotretinoin and tretinoin added to the culture resulted in the lowest percentage of PCNA positive cells. However, the lowest fraction of Ki 67 positive cells was observed after addition of isotretinoin. The obtained results also confirm the fact that the well-known regulatory proteins Bcl-2 and p53 play an important role in the regulation of apoptosis in the MCF-7 cell line, with lowered Bcl-2 expression accompanying easier apoptotic induction. The majority of the examined compounds act via the p53 pathway although some bypass this important proapoptotic factor.
Acta Biochim Pol 2004
PMID:Can transforming growth factor-beta1 and retinoids modify the activity of estradiol and antiestrogens in MCF-7 breast cancer cells?. 1544 35

Cyclin-dependent kinases (CDKs) are serine/threonine kinases that play a key role in the regulation of the cell cycle progression. In proliferating cells, distinct CDKs activated upon complexing with specific cyclins and upon site-specific phosphorylation coordinate in an orchestrated way the appropriate transition between consecutive phases of the cell cycle. Aberrant expression or altered activity of distinct CDK complexes results in escape of cells from the cell cycle control and leads to malignant transformation. Therefore, the inhibition of CDKs in malignant cells provides a new strategy in the fight against cancer. Recently, selective CDK inhibitors targeting distinct CDKs were developed. They represent promising anti-cancer drugs due to their strong anti-proliferative efficacy combined with a relative low direct cytotoxicity. The aim of this study was to compare the effect of two related CDK inhibitors: roscovitine (ROSC) and olomoucine (OLO) on the cell cycle progression in human breast cancer MCF-7 cells. Both examined CDK inhibitors differentially affected the cell cycle progression in MCF-7 cels. Whereas ROSC arrested cells in G(2)/M, OLO inhibited cells at S to G(2) transition and increased the number of cells residing in the S-phase. Moreover, both CDK inhibitors modulated the cell cycle progression with distinct kinetics. Accumulation of G(2)/M-arrested cells beginning 6 h after exposure of cells to ROSC coincided with a strong up-regulation of the p53. Interestingly, ROSC triggered apoptosis in MCF-7 cells by activation of mitochondrial pathway. Loss of the integrity of mitochondrial membrane observed after exposure of cells to ROSC for 6 h led to release of distinct mitochondrial proteins, e.g. apoptosis inducing factor (AIF). In contrast to ROSC, OLO-induced cell cycle changes could be detected after 12 h of the treatment. OLO did not up-regulate p53 protein. It indicates that both examined CDK inhibitors are selective and block the cell cycle progression of human breast carcinoma cells at different phases.
Pol J Pharmacol
PMID:Cell cycle arrest induced in human breast cancer cells by cyclin-dependent kinase inhibitors: a comparison of the effects exerted by roscovitine and olomoucine. 1559 54


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