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)

The biological activity of a novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) was investigated in human breast carcinoma (HBC) cells. Although capable of selective binding to the RAR gamma nuclear receptor, AHPN inhibited the growth of a number of HBC cell lines via RAR- or RXR-independent pathways. AHPN also inhibited the growth of the human leukemia cell line HL-60R which does not possess functional RARs. RA significantly inhibited AP-1 mediated gene activation in MCF-7 cells while AHPN displayed no such anti-AP-1 activity. Retinoids normally are cytostatic in their inhibition of breast carcinoma growth and permit cell proliferation upon their removal, wher as AHPN induced G0/G1 arrest within 6h followed by apoptosis. In MCF-7 cells that harbor wild type p53, AHPN-induced G0/G1 arrest and apoptosis was accompanied by p53-independent regulation of WAF1/CIP1 as well as bax mRNA levels while bcl-2 mRNA levels were decreased. In MDA-MB-231 cells which possess a mutant p53, AHPN-mediated G0/G1 arrest and apoptosis was also associated with a concomitant up regulation of WAF1/CIP1 mRNA while these cells did not express bax or bcl-2 messages. Thus AHPN represents a novel retinoid that induces G0/G1 arrest and apoptosis via a unique pathway which appears to involve activation of known downstream effectors of p53 in a p53-independent manner.
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PMID:p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. 763 Jun 33

Cellular senescence is characterized by a finite proliferative capacity in vitro. Moreover, the proliferative capacity of dermal fibroblasts harvested from humans is inversely proportional to the age of the donor, suggesting that senescence in culture is a manifestation, at the cellular level, of processes that occur during in vivo human aging. As cellular senescence is a program that ultimately decreases cell proliferation, it has been hypothesized that the genetic mechanisms responsible for the negative growth regulation of senescence may also be involved in the suppression of neoplastic transformation. Retinoic acid (RA) and its derivatives are effective negative growth regulators and are known to inhibit tumor growth, in vitro and in vivo. As a first step in examining a role for retinoic acid in the regulation of cellular aging in human fibroblasts, we examined the expression of the nuclear receptors for RA (RAR alpha, RAR beta, and RAR gamma) in human donors of different ages. These studies demonstrate a selective up-regulation of RAR beta, in response to RA, in fibroblasts that manifest a decreased proliferative capacity. We extend these observations to show that this finding is independent of the age of the donor and correlates with the proliferative capacity of the culture as a whole. Nuclear run-on studies show that the increase in RAR beta mRNA accumulation is mediated by a striking increase in the transcription of the RAR beta 2 isoform. Senescent fibroblasts manifesting the transcriptional increase of the RAR beta 2 isoform also demonstrate transcriptional repression of the protooncogene, c-fos. Functional studies demonstrate that RAR beta 2, like the tumor suppressor gene p53, can inhibit oncogene-induced focus formation. These data provide further support for the contention that genetic events important in cellular senescence may also play a significant role in tumor suppression in humans. Moreover, these observations suggest that RA, through transcriptional regulation of RAR beta 2, may mediate aspects of the negative growth control that characterizes both states.
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PMID:Cellular aging and transformation suppression: a role for retinoic acid receptor beta 2. 773 67

Retinoic acid inhibits the growth of a variety of normal and transformed cells in vitro and in vivo. How retinoic acid inhibits cell growth is poorly understood but involves interactions between the ligand and a series of nuclear and cytoplasmic receptors. The nuclear receptors for retinoic acid are of two types, the RARs and the RXRs. Each can function as a ligand-inducible transcription enhancing factor. In previous studies, we have demonstrated that an isoform of one RAR, RAR beta 2, is transcriptionally up-regulated in senescent human dermal fibroblasts and senescent human mammary epithelial cells. Moreover, we have also shown that RAR beta 2 can inhibit oncogene-induced focus formation, in primary rat embryo fibroblasts, as effectively as the tumor suppressor gene p53. Here, we extend our studies of retinoid-regulated signal transduction pathways that inhibit cell proliferation by demonstrating that HeLa cells expressing an RAR beta 2 construct are growth inhibited by greater than 50% when compared to the parent cell lines. The RAR beta 2-expressing cell lines are inhibited further by the addition of exogenous all-trans-retinoic acid. Finally, soft agar assays show that the RAR beta 2-expressing cell lines also demonstrate an inhibition of growth in soft agar, when compared to the parent growth cell lines, and are inhibited further in the presence of added all-trans-retinoic acid. These data definitively show that RAR beta 2 can inhibit cell proliferation in an established tumor cell line and provide more strength to the notion that this isoform is an effective growth inhibitor in vitro and, most likely, in vivo.
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PMID:RAR beta 2-mediated growth inhibition in HeLa cells. 863 81

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

In this study, we investigated the effect of the novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) on the growth of human lung carcinoma cell lines. AHPN inhibits the proliferation of all cell lines tested, irrespective of the lung tumor type, in a concentration- and time-dependent manner. A dramatic reduction in cell number was observed in adenocarcinoma H460 cells, and was shown to be related to an induction of apoptosis. Bromodeoxyuridine (BrdU) incorporation and flow-cytometric analyses indicated that treatment of H460 cells with AHPN induces cell-cycle arrest at the G1 phase. We therefore investigated the effect of AHPN on several regulatory proteins of the G1 phase of the cell-cycle. The cell-cycle arrest induced by AHPN was accompanied by an inhibition of the hyperphosphorylation of the retinoblastoma (Rb) protein, an indication of G1 arrest. Furthermore, two cyclin-dependent kinases, cdk2 and cdk4, which are normally involved in the phosphorylation of Rb, were shown to have decreased activity. In some cell lines, the decrease in cdk activity may be partly related to an increase in p21(WAF1/Cip1) (p21), an inhibitor of cyclin-dependent kinases. No changes were observed in the cyclin-dependent kinase inhibitor p27(Kip1). The observed increase in p53 in response to AHPN could at least to some extent be responsible for the increased levels of p21. The increase in p53 expression was found to be regulated at a post-transcriptional level. Our results suggest that the growth inhibition of certain lung carcinoma cell lines by AHPN is at least partly related to an increase in p21. However, in other cell lines, different mechanisms appear to be involved. The specificity with which AHPN and other retinoids induce growth arrest and p21 expression indicates that the action of AHPN is not mediated by RAR or RXR receptors, but involves a novel signaling pathway.
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PMID:Inhibition of cell proliferation and induction of apoptosis by the retinoid AHPN in human lung carcinoma cells. 949 Jun 50

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

Ro 41-5253 is a RARalpha-selective antagonist that binds RARalpha but does not induce transcriptional activation and does not influence RAR/RXR heterodimerization and DNA binding. This retinoid inhibits proliferation and induces apoptosis in MCF-7 and ZR-75.1 estrogen-receptor-positive breast-carcinoma cells in a dose-dependent way. The anti-proliferative effect is more evident in ZR-75.1 cells than in MCF-7 cells and is probably mediated by anti-AP1 activity, a mechanism known to be implied in the action of several retinoids. In the induction of apoptosis also ZR-75.1 cells are more sensitive to treatment with Ro 41-5253 than MCF-7 cells. In ZR-75.1 cells an apoptotic/hypodiploid DNA peak is already evident after 2 days of incubation, whereas in MCF-7 cells it appears only after 4 days. The highest percentage of apoptotic cells, for both cell lines, is reached after 6 days of treatment. The apoptosis pathway is p53-independent and bcl-2 downregulation seems to be correlated with an increase in TGF-beta1 protein. The MDA-MB-231 estrogen-receptor-negative cell line is poorly responsive to Ro 41-5253 treatment, both in terms of proliferation inhibition and apoptosis induction. Ro 41-5253 has proliferation-inhibiting and apoptosis-inducing properties that are not mediated by transcriptional activation from retinoic-acid response elements. This retinoid antagonist seems to be a compound that exerts an anti-tumor activity but does not induce the toxic side effects of retinoids and might, therefore, be considered as a candidate for cancer therapy.
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PMID:RARalpha antagonist Ro 41-5253 inhibits proliferation and induces apoptosis in breast-cancer cell lines. 972 98

Although retinoids have proven to be effective as chemopreventive agents in reversing premalignant oral lesions and preventing second primary tumors, their mechanisms of chemopreventive efficacy in clinical settings have not been established. To better define this mechanism, we studied p53 protein and retinoic acid receptor beta (RAR-beta) expression in 52 baseline biopsy samples taken from premalignant oral lesions. We then studied p53 expression in 39 matched samples and RAR-beta expression in 38 matched samples before and after treating them with isotretinoin. The study results were then compared with clinical responses. To detect p53 protein expression, 4-micrometer sections of formalin-fixed, paraffin-embedded tissue specimens were used for immunohistochemical analysis with a monoclonal anti-p53 antibody, and levels of p53 expression were recorded with a labeling index (LI). Expression of RAR-beta mRNA was determined using nonradioactive in situ hybridization, and the staining intensity of RAR-beta mRNA was semiquantitated using scores from 0 (no expression) to 3+ (highest expression). p53 protein was detected in 85% of all lesions. High p53 protein expression (LI >/= 0.2) was detected in 25% of the lesions at baseline and in 18% of the lesions after isotretinoin therapy. The clinical response was 65% for lesions having low p53 expression (LI < 0.2) and 27% for lesions having high p53 expression (P = 0.027). Expression of RAR-beta mRNA was detected in 40% of the patients at baseline and increased to 90% of the patients after isotretinoin therapy (P < 0. 001). Seventy-two percent of the patients having low p53 expression had no RAR-betamRNA expression at baseline, whereas 22% of the patients having high p53 expression had no RAR-beta expression, which suggests that patients having low p53 expression tended to lose RAR-beta mRNA expression in their tissues. Eighty-three percent of patients having low p53 expression had up-regulation of RAR-beta mRNA after isotretinoin therapy, compared with 22% of patients with high p53 expression (P = 0.003). We correlated baseline p53 protein expression with RAR-beta modulation and clinical responses to isotretinoin therapy. The patients with low p53 protein expression at baseline and up-regulation of RAR-beta after isotretinoin therapy achieved a 70% rate of major response. The patients with low p53 protein expression and either no change or down-regulation of RAR-beta or with high p53 expression and up-regulation of RAR-beta had a response rate of 50%. The patients with high p53 protein expression and either no change or down-regulation of RAR-beta had a response rate of only 14% to isotretinoin therapy. The basic mechanisms underlying the association between clinical responses and these two biomarkers need to be explored.
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PMID:Accumulation of p53 protein and retinoic acid receptor beta in retinoid chemoprevention. 981 62

We previously reported that mice lacking the RARgamma gene and one or both alleles of the RARbeta gene (i.e., RARbeta+/-/RARgamma-/- and RARbeta-/-/RARgamma-/- mutants) display a severe and fully penetrant interdigital webbing (soft tissue syndactyly), caused by the persistence of the fetal interdigital mesenchyme (Ghyselinck et al., 1997, Int. J. Dev. Biol. 41, 425-447). In the present study, these compound mutants were used to investigate the cellular and molecular mechanisms involved in retinoic acid (RA)-dependent formation of the interdigital necrotic zones (INZs). The mutant INZs show a marked decrease in the number of apoptotic cells accompanied by an increase of cell proliferation. This marked decrease was not paralleled by a reduction of the number of macrophages, indicating that the chemotactic cues which normally attract these cells into the INZs were not affected. The expression of a number of genes known to be involved in the establishment of the INZs, the patterning of the autopod, and/or the initiation of apoptosis was also unaffected. These genes included BMP-2, BMP-4, Msx-1, Msx-2, 5' members of Hox complexes, Bcl2, Bax, and p53. In contrast, the mutant INZs displayed a specific, graded, down-regulation of tissue transglutaminase (tTG) promoter activity and of stromelysin-3 expression upon the removal of one or both alleles of the RARbeta gene from the RARgamma null genetic background. As retinoic acid response elements are present in the promoter regions of both tTG and stromelysin-3 genes, we propose that RA might increase the amount of cell death in the INZs through a direct modulation of tTG expression and that it also contributes to the process of tissue remodeling, which accompanies cell death, through an up-regulation of stromelysin-3 expression in the INZs. Approximately 10% of the RARbeta-/- /RARgamma-/- mutants displayed a supernumerary preaxial digit on hindfeet, which is also a feature of the BMP-7 null phenotype (Dudley et al., 1995, Genes Dev. 9, 2795-2807; Luo et al., 1995, Genes Dev. 9, 2808-2820). BMP-7 was globally down-regulated at an early stage in the autopods of these RAR double null mutants, prior to the appearance of the digital rays. Therefore, RA may exert some of its effects on anteroposterior autopod patterning through controlling BMP-7 expression.
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PMID:Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods. 1007 39

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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