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)

Pancreatic cancer has one of the worst prognoses of all human malignancies and the molecular mechanisms underlying this aggressive disease have been extensively investigated in the past years. Tyrosine kinase growth factor receptors and their ligands act to influence tumor cell growth, differentiation, invasion, metastasis, and angiogenesis. In pancreatic cancer a variety of these growth factor receptors and ligands are expressed at increased levels and this overexpression influences the clinical course of the disease. For example, the concomitant presence of the EGF receptor and its ligands EGF, TGF-alpha, and/or amphiregulin is associated with enhanced tumor aggressiveness and shorter survival periods following tumor resection. Furthermore, the growth inhibitory effects of the TGF-beta superfamily of serine-threonine kinase receptors and their ligands are often blocked in pancreatic cancer cells. In addition to these alterations, mutations of the p53 tumor-suppressor gene, the K-ras proto-oncogene, and the Smad4 gene are frequently present in these tumors. Taken together, the abundance of growth-promoting factors, the disturbance of growth inhibitory pathways, and the presence of gene mutations combine to give pancreatic cancer cells a distinct growth advantage which clinically results in rapid tumor progression and poor survival.
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PMID:Molecular aspects of pancreatic cancer and future perspectives. 1044 72

The oncogene product epidermal growth factor receptor (EGF-R), the tumour suppressor gene product p53 and anti-p53 antibodies are detectable in the serum of certain cancer patients. Increased levels of some of these products were reported in lung cancer patients after occupational asbestos exposure and after exposure to polycyclic aromatic hydrocarbons or vinylchloride. In the first step, this study investigated the possible diagnostic value of serum EGF-R, p53-protein and anti-p53 antibodies, measured by an enzyme-linked immunosorbent assay, in lung tumour patients. In addition to being investigated on a molecular epidemiological basis, these parameters were examined as biomarkers of carcinogenesis, especially with regard to asbestos incorporation effects or of radon-induced lung cancers. Also, a possible effect of cigarette smoking and age dependence were studied. A total of 116 male patients with lung or pleural tumours were examined. The histological classification was four small-cell cancers, six large-cell cancers, 32 adenocarcinomas, 47 squamous carcinomas, 12 mixed lung carcinomas, five diffuse malignant mesotheliomas and ten lung metastasis of extrapulmonary tumours. Twenty-two lung cancers and all mesotheliomas were related to asbestos, 22 lung cancers were related to ionizing radiation and 61 patients had cigarette smoke-related lung cancer. Besides these patients 50 male patients with non-malignant lung or pleural diseases were included; of the latter eight subjects suffered from asbestosis. Controls were 129 male subjects without any lung disease. No significantly elevated or decreased serum values for p53 protein, EGF-R, or anti-p53 antibodies as a function of histological tumour type, age, or degree and type of exposure (asbestos, smoking, ionizing radiation) could be found. The utility of p53-protein, EGF-R and anti-p53 antibodies as routine biomarkers for screening occupationally derived lung cancers is limited.
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PMID:p53 protein, EGF receptor, and anti-p53 antibodies in serum from patients with occupationally derived lung cancer. 1047 Oct 51

Gene amplification and enhanced expression of the epidermal growth factor receptor (EGFR) represent the major molecular genetic alteration in glioblastomas and it may play an essential role in cell growth and in the carcinogenic process. On the other hand, the nuclear suppressor proteins PML and p53 are also known to play critical roles in cancer development and in suppressing cell growth. Here we report that, in glioblastoma cells with defective EGFR function, the expressions of both promyelocytic leukaemia (PML) and p53 were altered. Cells that were transfected with the antisense-cDNA of EGFR were found to have more cells in G1 and fewer cells in S phase. In addition, the transfected cells were found to be non-responsive to EGF-induced cell growth. Interestingly, the expression of the suppressors p53 and PML were found to be significantly increased by immunohistochemical assay in the antisense-EGFR cells. Moreover, the PML expression in many of the cells was converted from the nuclear dot pattern into fine-granulated staining pattern. In contrast, the expressions of other cell cycle regulated genes and proto-oncogene, including the cyclin-dependent kinase 4 (cdk4), retinoblastoma, p16INK4a and p21H-ras, were not altered. These data indicate that there are specific inductions of PML and p53 proteins which may account for the increase in G1 and growth arrest in antisense-EGFR treated cells. It also indicates that the EGF, p53 and PML transduction pathways were linked and they may constitute an integral part of an altered growth regulatory programme. The interactions and cross-talks of these critical molecules may be very important in regulating cell growth, differentiation and cellular response to treatment in glioblastomas.
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PMID:Altered expression of the suppressors PML and p53 in glioblastoma cells with the antisense-EGF-receptor. 1057 56

Carcinoma of the breast has an unpredictable biological behaviour. Several oncogenes have been implicated in the progression of breast cancer. Immunohistochemical staining of c-erbB-2 (Neu) oncoprotein and mutant p53 protein on 45 cases of infiltrating duct carcinoma (IDC) of the breast revealed 33% membrane positivity of c-erbB-2 oncoprotein, 46% nuclear positivity of mutated p53 protein, 33% and 84% membrane positivity of EGF-R and EMA respectively. Staining profile of c-erb-B2 oncoprotein in various histological subtypes of IDC of the breast indicated a high positivity rate in comedo followed by NOS and cibriform subtype. Similarly, high incidence of immunopositivity of mutated p53 protein was observed in comedo and cibriform subtypes while papillary carcinoma were found exclusively positive for mutated p53 protein. Interestingly, tubular subtype of IDC was not positive for c-erbB-2 oncoprotein as well as p53 mutant protein. Further, comedo and cibriform subtypes of IDC revealed 'high grade' histological features of tumour of the breast with high mitotic count, presence of marked pleomorphism and multinucleation thus, reflecting a positive relationship with overexpression of c-erbB-2 (Neu) oncoprotein as well as mutant p53 protein. The results on immunoexpression of c-erbB-2 oncoprotein and mutated p53 protein in various histological subtypes of IDC of the breast demonstrated c-erbB-2 status as an important predictor and also indicated that oncogene product may be involved in growth factor response pathway.
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PMID:Immunohistochemical co-expression of c-erbb-2/Neu oncoprotein, altered tumour suppressor (p53) protein, EGF-R and EMA in histological subtypes of infiltrating duct carcinoma of the breast. 1064 Nov 49

Pancreatic cancer represents the fourth leading cause of cancer death in men and the fifth in women. Prognosis remains dismal, mainly because the diagnosis is made late in the clinical course of the disease. The need to improve the diagnosis, detection, and treatment of pancreatic cancer is great. It is in this type of cancer, in which the mortality is so great and the clinical detection so difficult that the recent advances of molecular biology may have a significant impact. Genetic alterations can be detected at different levels. These alterations include oncogene mutations (most commonly, K-ras mutations, which occur in 75% to more than 95% of pancreatic cancer tissues), tumour suppressor genes alterations (mainly, p53, p16, DCC, etc.), overexpression of growth factors (such as EGF, TGF alpha, TGF beta 1-3, aFGF, bTGF, etc.) and their receptors (i.e., EGF receptor, TGF beta receptor I-III, etc.). Insights into the molecular genetics of pancreatic carcinogenesis are beginning to form a genetic model for pancreatic cancer and its precursors. These improvements in our understanding of the molecular biology of pancreatic cancer are not simply of research interest, but may have clinical implications, such as risk assessment, early diagnosis, treatment, and prognosis evaluation.
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PMID:Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes, growth factors, and their receptors from a clinical perspective. 1066 Apr 90

Pancreatic cancer cells are usually resistant to apoptosis induced by cytotoxic drugs, by activation of surface receptors such as Fas and TNF receptor or by serum or growth factor withdrawal. Actinomycin D (actD) is an inhibitor of RNA synthesis and acts as a potent inducer of apoptosis in several cell lines. In the present study, we investigated the effects of actD on PANC-1 pancreatic cancer cells. ActD caused apoptosis in PANC-1 cells in a dose-dependent manner, as determined by cell growth assays, DNA laddering and TUNEL assays. Induction of apoptosis correlated with activation of the JNK/SAPK pathway and increased expression of Bax but not Bad or p53. PANC-1 cells were completely resistant to Fas antibody and TNF-alpha. In contrast, TRAIL decreased the growth of PANC-1 cells by 22%. Low concentrations of actD (10 ng/ml) enhanced the cytotoxic effects of all 3 cytokines. EGF, FGF-2 and IGF-I did not protect PANC-1 cells from actD-mediated apoptosis. ActD (10 ng/ml) also inhibited the growth of CAPAN-1 and T3M4 pancreatic cancer cells but not MiaPaCa-2 cells. Our observations suggest that actD may act via JNK/SAPK and Bax to promote apoptosis in PANC-1 cells and that it may inhibit the growth of other pancreatic cancer cell lines.
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PMID:Actinomycin D induces apoptosis and inhibits growth of pancreatic cancer cells. 1076 Aug 29

Two prostatic epithelial lines, one of basal origin and one of luminal origin, were established from the dorsolateral prostates of p53 null mice. The cell lines are nontumorigenic when inoculated subcutaneously under the renal capsule or intraprostatically in syngeneic mice. The luminal cell line (PE-L-1) expresses cytokeratins 8 and 18 and the basal cell line (PE-B-1) expresses cytokeratins 5 and 14. The basal cells require serum for growth, whereas the luminal cells grow only in serum-free medium. Both cell lines require the presence of growth factors for optimal growth in culture, with EGF and FGF-2 having the greatest effect on the growth rate. Both lines express androgen receptor (AR) mRNA and protein. Androgen stimulates growth of the basal cell line, indicating that the ARs are functional, whereas growth of the luminal cells is unaffected by androgens. The luminal line is significantly inhibited by exogenous TGF-beta and produces low levels of endogenous TGF-beta. In contrast, the basal cell line produces significant amounts of TGF-beta and its growth is not influenced by this cytokine. Coculture of luminal cells with prostatic smooth muscle cells results in the generation of increased levels of biologically active TGF-beta, indicating a paracrine mechanism of TGF-beta activation that may be involved in the maintenance of normal prostatic function. To our knowledge this is the first report describing both basal and luminal prostatic cell lines from a single inbred animal species and the first indication that prostatic epithelial and stromal cells interact to generate the biologically active form of TGF-beta. These lines will provide an important model for determining basal/luminal interactions in both in vitro and in vivo assays.
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PMID:Generation of active TGF-beta by prostatic cell cocultures using novel basal and luminal prostatic epithelial cell lines. 1082 35

Two hundred eighty nine pT1a/pT1b (less than < or = 1 cm in diameter) mammary carcinomas were selected from a series of 2077 consecutive cases of breast carcinoma. When compared with carcinomas of a larger size, they were significantly associated with a lower histological grade (SBR), a lower growth fraction (Ki-67 antigen in less than 20% of neoplastic cells) and a lower number of positive cases (more than 10% of neoplastic cells) as far as p53, c-erbB-2 oncoproteins and EGF-R, as detected by immunohistochemical methods, are concerned. Moreover, a significantly higher number of estrogen and progesterone receptors positive cases (more than 10% of positive cells), and a higher frequency of "other" histotypes with a favourable prognosis, was detected. No difference between pT1a and pT1b cases was noted so that "1 cm size" only stratifies a class with a better prognosis. It is possible that small cases, although invasive, did not undergone sufficient mytotic cycles to produce the sequence of genetic changes that characterize the "no return" phase of breast cancer. A 17% of pT1a and pT1b cases displayed lymph node metastases (mean 26 lymph node/case examined): the number is so high that cautions about simple lumpectomies and about sentinel lymphadenectomy, even in cases of small cancers, are necessary, until a larger number of studies will become available.
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PMID:[Biomorphological features of "minimal" carcinomas selected from a series of 2077 breast cancer cases]. 1083 70

Addition of growth factors such as EGF and insulin to serum-starved G(0) Chinese hamster fibroblast cells results in activation of the phosphatidylinositol 3-kinase (PI3-K)/p70 S6 kinase (p70(S6K)) pathway and the ras-raf mitogen-activated kinase (MAPK) pathway. Activation of these pathways is usually associated with protection of cells from apoptosis. We have studied the effect of three alkylpurines, O(6)-methylguanine (O6meG), O(6)-ethylguanine (O6etG) and 6-dimethylaminopurine (6DMAP) on two particular steps of these pathways, namely activation of p70(S6K) and of MAPK. Under the same experimental conditions we studied the ability of these alkylpurines to induce apoptosis. Our results show that the three alkylpurines induced apoptosis with increasing efficiency from O6meG to 6DMAP to O6etG. The induction of apoptosis was phase specific, with the G(0)/G(1) phase being most sensitive. A reduced apoptotic response was observed in cells with abnormal nuclear accumulation of mutant or wild-type p53, suggesting that functional p53 was required for the induction of apoptosis. At concentrations inducing apoptosis the three alkylpurines inhibited p70(S6K) activity, while they had the opposite effect on MAPK. Rapamycin, a specific inhibitor of the p70(S6K) pathway, did not induce apoptosis at doses inhibiting p70(S6K) activity, suggesting that p70(S6K) is not directly involved in apoptosis. As expected, and in line with results reported by others, wortmannin, an upstream inhibitor of the p70(S6K) pathway, did induce apoptosis. We propose that activation of the MAPK pathway and simultaneous inhibition of the p70(S6K) pathway induce an apoptotic response in the cell.
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PMID:Induction of apoptosis and inhibition of signalling pathways by alkylated purines. 1088 17

Depsipeptide, FR901228, a novel cyclic peptide inhibitor of histone deacetylase with a unique cytotoxicity profile is currently in phase I clinical trials. Here we demonstrate that, in addition to G2/M arrest, FR901228 causes G1 arrest with Rb hypophosphorylation. In vitro kinase assays demonstrated no direct inhibition of CDK activity, however, an inhibition was observed in CDKs extracted from cells exposed to FR901228. Cyclin D1 protein disappeared between 6 and 12 hours after treatment with FR901228, whereas cyclin E was upregulated. While it did not induce wt p53, FR901228 did induce p21(WAF1/CIP1)in a p53-independent manner. Cell clones lacking p21 were not arrested in G1 phase, but continued DNA synthesis and were arrested in G2/M phase following FR901228 treatment. Finally, FR901228 blunted ERK-2/MAPK activation by EGF whereas early signal transduction events remained intact since overall cellular tyrosine phosphorylation after EGF stimulation was unaffected. Thus, FR901228, while not directly inhibiting kinase activity, causes cyclin D1 downregulation and a p53-independent p21 induction, leading to inhibition of CDK and dephosphorylation of Rb resulting in growth arrest in the early G1 phase. In contrast to the G1 arrest, the G2/M arrest is p21-independent, but is associated with significant cytotoxicity.
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PMID:P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. 1095 88


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