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)

More than 90% of epithelial ovarian cancers arise from single cells. Malignant transformation can be associated with a number of molecular alterations including upregulation of tyrosine kinases and phosphatases, physiologic activation o ras, mutation of p53, amplification of myc, and increased activity of matrix metalloproteinases 2 and 9. Proliferation of transformed epithelial cells can be enhanced through the persistence of autocrine growth stimulation by TGF-alpha, loss of autocrine growth inhibition by TGF-beta, as well as paracrine growth stimulation by macrophage derived cytokines and OCAF, a novel lyso-phospholipid. Ascites tumor cells retain responsiveness to growth inhibition by TGF-beta which induces apoptosis in malignant ovarian epithelial cells, but not in normal ovarian surface epithelium. Proliferation of surface epithelial cells following ovulation may contribute to the pathogenesis of ovarian cancer. Use of oral contraceptives that suppress ovulation has been associated with reduced risk of ovarian cancer in later life. Retinoids also deserve further evaluation for chemoprevention. Treatment with fenretinide was associated with decreased incidence of ovarian cancer. Additive or synergistic inhibition of ovarian tumor cell proliferation has been observed with TGF-beta in combination with all-trans-retinoic acid. Early detection of ovarian cancer could improve survival. Transvaginal sonography (TVS) and serum markers such as CA-125 have been evaluated in multiple clinical trials. The former lacks adequate specificity, whereas the latter is not sufficiently sensitive. Use of multiple serum markers can improve sensitivity. A combination of CA-125, M-CSF and OVX-1 has detected > 95% of Stage I ovarian cancers. If similar results are obtained with different data sets, multiple serum markers could be used to trigger the performance of TVS, providing a potentially cost effective screening strategy. Prospective trials will be required to demonstrate that screening for early stage ovarian actually impacts on survival.
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PMID:Molecular approaches to prevention and detection of epithelial ovarian cancer. 874 99

Retinoids mediate the normal growth of a variety of epithelial cells and may play an important role in the chemoprevention of certain malignancies. Loss of retinoic acid (RA) receptor-beta function may be an important event in mammary carcinogenesis, because the majority of breast cancers, in contrast to normal mammary epithelial cells, fail to express this receptor. We previously reported that all-trans-RA mediates G1 arrest as well as apoptosis in certain RAR beta-transduced breast cancer cell lines. We now report the effect of RA on normal human mammary epithelial cells (HMECs), which express functionally active retinoid receptors. We observe that RA induces growth suppression and G1 arrest of these HMECs but find no evidence that RA mediates apoptosis in these normal cell strains. This RA-induced G1 arrest is temporally associated with decreased levels of hyperphosphorylated retinoblastoma protein without any significant changes in c-myc, p53, p21, or p27 expression. Expression of cyclin D1, cyclin-dependent kinase 4, and cyclin E proteins, however, decreased in association with RA-mediated G1 arrest. Our studies suggest that growth inhibition, rather than apoptosis, may be a mechanism by which RA and RA receptors act to prevent the malignant transformation of normal mammary epithelial cells. The molecular target(s) of the activated RA receptors that mediate this G1 arrest in HMECs appear to be associated with a retinoblastoma-dependent pathway.
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PMID:All-trans-retinoic acid mediates G1 arrest but not apoptosis of normal human mammary epithelial cells. 918 97

The relation between resistance to anticancer drugs and resistance to apoptosis has been investigated in the human leukemic cell line(KY-821) and its drug-resistant sublines. Under serum depletion conditions, drug-resistant cell lines showed apoptotic resistance when compared with the parental cell line. Drug resistant cell lines also showed resistance to apoptosis when treated with all-trans retinoic acid. DNA fragmentation was low in drug resistant cell lines under both stimulations. Flowcytometry analysis did not show any alterations of the Fas antigen, p53, bcl-2 and c-myc protein expression toward inhibition of apoptotic response in drug-resistant sublines. These results indicate that drug-resistant leukemic cells still show resistance to apoptosis-inducing stimulation such as poor nutrition and differentiation-inducing agents.
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PMID:Resistance to apoptosis induced by serum depletion and all-trans retinoic acid in drug-resistant leukemic cell lines. 932

Testicular germ tumor cells could be differentiated spontaneously or by some chemotherapeutic compounds. However, the mechanism by which the cells are differentiating from the stem cell remains unclear. The KU-MT cells, which were newly established from lung metastasis of testicular carcinoma, have been continuously producing alpha fetoprotein (AFP). Retinoic acids are well-known to induce cellular differentiation in culture and have already been applied for a clinical usage against leukemia. In the present study, all-trans-retionic acid (ATRA) elevated the level of AFP and inhibited the growth of KU-MT cells in vitro. ATRA also arrested the cell cycle in G1 and reduced the percentage of the S phase cell in terms of wild type p53, leading to apoptosis in part. Retinoids, especially retinoic acid receptor (RAR)-alpha specific agonists induced laminin production, a marker of endodermal differentiation; whereas arotinoid, a retinoid not bound to RAR-alpha, did not affect laminin expression. In summary, retinoic acids could mediate cell growth and differentiation of testicular tumor through RAR-alpha.
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PMID:[Retinoic acid-induced cell growth inhibition and differentiation in testicular carcinoma cells in culture]. 943 34

Most human non-small cell lung cancer (NSCLC) cell lines are refractory to all-trans-retinoic acid (ATRA). Recently, N-(4-hydroxyphenyl)retinamide (4HPR) was found to induce apoptosis in various tumor cells. In this study, we compared and contrasted the effects of 4HPR and ATRA on the growth and apoptosis of 10 NSCLC cell lines and normal human bronchial epithelial (NHBE) cells. All of the cancer cell lines and the NHBE cells were sensitive to 10 microM 4HPR, and their numbers decreased to <20% of the controls after a 5-day treatment, whereas ATRA decreased cell numbers to about 50% of the controls in three cell lines and was less effective in the rest of the tumor cell lines. ATRA inhibited the growth of the NHBE cells by 70-80%. 4HPR induced apoptosis in most of the cells, including the ATRA-resistant ones, as evidenced by a DNA fragmentation assay. No correlation was found between growth inhibition by 4HPR and the expression of retinoic acid receptor beta (determined by Northern blotting and PCR), p53, or Bcl-2 proteins (analyzed by Western blotting). These results demonstrate that 4HPR is more potent than ATRA in inducing apoptosis in NSCLC cells and suggest that further clinical trials for prevention and therapy of NSCLC using 4HPR are warranted.
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PMID:Higher potency of N-(4-hydroxyphenyl)retinamide than all-trans-retinoic acid in induction of apoptosis in non-small cell lung cancer cell lines. 960 96

Adult T-cell leukemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Despite the administration of combined intensive chemotherapy, the reported survival time of patients with acute and lymphoma types of ATL is less than 10 months. We therefore examine the effects of all-trans-retinoic acid (ATRA), 9-cis-RA and 13-cis-RA and tried to elucidate the mechanisms of inducing growth inhibition and apoptosis by these RAs using four ATL cell lines established in our laboratory. All the investigated RAs inhibited cell growth and the cells were arrested at the G1 phase. Apoptosis was induced in three out of four cell lines. Among the growth regulatory proteins examined, the level of p21Waf1/Cip1 protein was found to increase after RA treatment, thus resulting in pRb hypophosphorylation which also induced the arrest of the cells at the G1 phase. In addition, the p53 level decreased at the same time. Fas-FasL system and the downregulation of CD25 (IL-2R/alpha) expression did not seem to be involved. Based on these findings, the ability of RAs to induce a remission of ATL is thus strongly suggested.
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PMID:Retinoic acids induce growth inhibition and apoptosis in adult T-cell leukemia (ATL) cell lines. 968 Jan 11

Retinoids, including natural vitamin A and its analogs, have been closely studied as chemopreventive drugs. The mechanism of action of retinoids, however, is not completely understood. Our study evaluated the effects of all-trans (high affinity ligand for both RAR and RXR receptors) and 9-cis retinoic acid (binds only with RXR receptors) on E6-E7 transcription, cell proliferation, cell cycle distribution, and p53 expression in CaSki cells, a cell line derived from cervical carcinoma containing 600 copies of the HPV-16 genome. Using quantitative RT-PCR analysis, we found that CaSki cells treated with all trans retinoic acid (ATRA) for seven days had a remarkably low level of E6-E7 transcription at 10(-5) M to 10(-9) M concentrations. A smaller inhibitory effect was observed on the E6-E7 transcription at a concentration of 10(-5) M with only 9-cis retinoic acid. Flow cytometric analysis revealed that cells treated with both all trans and 9-cis RA showed an increase in the mean percentage (93.5% and 86.1% respectively) of cells in the G1 phase as compared to untreated CaSki cells (55%) and normal keratinocytes (58%). The percentage of cells in the S phase decreased from a mean percentage of 28 and 26.5 to 5.8 and 5, respectively, after treatment with all trans retinoic acid and 9-cis retinoic acid. An increase in the level of immunophenotypic expression of wild type p53 was also noted after treatment with all trans retinoic acid and 9-cis retinoic acid. All trans and 9-cis retinoic acid may act on highly proliferating tumor cells by initially arresting DNA synthesis and inducing G1 arrest. In addition, they may be inducing a p53 dependent cell cycle arrest and thus suggests that all-trans and 9-cis retinoic acid may have a cytostatic effect rather than a cytotoxic effect on CaSki cells. The increased expression of p53 positive cells and the inhibition of E6/E7 transcription after treatment with these retinoids may indicate the potential role of all trans and 9-cis retinoic acid as a cell cycle regulator and an antiviral chemoprevention agent.
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PMID:The effect of all-trans and 9-cis retinoic acid on the steady state level of HPV16 E6/E7 mRNA and cell cycle in cervical carcinoma cells. 971 82

Observations based on overexpression of the suppressor gene p53 or interference with endogenous p53 support a role for p53 in mediating not only growth inhibition and apoptosis but also differentiation. The aim of this study was to characterize the mechanisms of p53-dependent differentiation in the monoblastic leukemia cell line U-937. These cells were transfected with a mutant of the p53 gene expressing wild-type p53 at a permissive temperature. The results showed that wild-type p53 and interferon (IFN)-gamma were able to work synergistically to promote differentiation. This cooperative response was not associated with early G1 arrest of the cell cycle, indicating that p53 can mediate differentiation by mechanisms other than those used for mediating G1 arrest. The differentiation response to transfected p53 with or without INF-gamma was inhibited by cyclic adenosine monophosphate (cAMP)-inducing agents (dibutyryl cyclic adenosine 3':5'-monophosphate, forskolin, and 3-isobutyl-1-methylxanthine) in a dose-dependent manner. In contrast, the differentiation response of p53-negative U-937 cells to 1,25-dihydroxychole-calciferol or all-trans retinoic acid was enhanced by cAMP-inducing agents at optimal concentrations and inhibited at higher concentrations. In addition, 1,25-dihydroxycholecalciferol-mediated differentiation could be achieved in cells arrested in G1 by concomitant incubation with cAMP-inducing agents, indicating that differentiation can occur in the absence of proliferation. In conclusion, the results of this study indicate that p53-dependent and -independent differentiation can occur independently of cell cycle regulation.
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PMID:p53-dependent and -independent differentiation of leukemic U-937 cells: relationship to cell cycle control. 976 44

Retinoids mediate the normal growth of a variety of epithelial cells and may play an important role in the chemoprevention of breast cancer. Despite the widespread clinical use of retinoids, specific target genes that are regulated by retinoids are relatively poorly characterized. We reported previously that all-trans-retinoic acid (ATRA) mediates G1-S-phase arrest in normal human mammary epithelial cells (HMECs). The tumor suppressor gene p53 is thought to be a critical regulator of G1-S-phase arrest mediated by DNA-damaging agents such as chemotherapy and radiation. The role of p53 protein expression in G1-S-phase arrest mediated by the differentiating agent ATRA is unknown. Increased expression of p53 protein is observed in ATRA-treated HMECs at 72 h; however, initiation of G1-S-phase arrest starts at 24 h, suggesting that this observed induction of p53 is a secondary event. Using retroviral-mediated gene transfer, we expressed the E6 protein of the human papillomavirus strain 16 (HPV-16) in HMECs. The HPV-16 E6 protein binds to p53 and targets it for degradation. Western analysis confirmed that HPV-16 E6-transduced HMECs had markedly decreased levels of p53 protein expression. Suppression of cellular p53 levels in HMECs did not alter the sensitivity of HMECs to ATRA-mediated growth arrest. Our studies suggest that ATRA-mediated G1-S-phase arrest is independent of the level of p53 protein expression. We also tested the ability of estrogen and antiestrogens to induce growth arrest in HMECs lacking p53 expression and found no decrease in the sensitivity of these cells to these agents. Our results emphasize the chemotherapeutic potential of ATRA and antiestrogens, particularly for suppressing the growth of tumors lacking functional p53.
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PMID:Retinoic acid-mediated G1-S-phase arrest of normal human mammary epithelial cells is independent of the level of p53 protein expression. 995 Feb 18

We treated primary epithelial cells from human normal prostate (NEPC) and prostate cancer (CEPC) with all-trans-retinoic acid (RA) to study whether it regulates the activity of tissue transglutaminase (tTGase), an enzyme that accumulates in cells undergoing apoptosis. tTGase activity was assessed by [14C]spermidine incorporation; tTGase, P53, Bcl-2, and p21 protein levels were evaluated by Western blotting; and RA receptors (RAR alpha, -beta, and -gamma), tTGase, retinol-binding protein (RBP), and cellular RBP type I transcripts were determined by semiquantitative RT-PCR. After 72-96 h of 10(-6) mol/L RA treatment, cell growth inhibition and apoptosis were associated with increased tTGase activity in both NEPC and CEPC, and with increased tTGase protein and messenger ribonucleic acid levels only in NEPC. Moreover, RA down-regulated RAR alpha and -beta and increased RBP messenger ribonucleic acid levels in NEPC, whereas it increased RAR beta gene expression and decreased Bcl-2 protein levels in CEPC. Our results suggest that RA induces tTGase gene expression and enzyme activity in normal prostate cells, and that RA-regulated pathways are impaired in cancer cells. Moreover, down-regulation of Bcl-2 protein and up-regulation of RAR beta suggest that retinoid may act on the genetic defect responsible for prostate cancer progression.
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PMID:Changes in tissue transglutaminase activity and expression during retinoic acid-induced growth arrest and apoptosis in primary cultures of human epithelial prostate cells. 1019 96


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