Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoic acid (RA) has been shown to be able to antagonize or synergize with phorbol 12-myristate 13-acetate (PMA). In contrast to its antagonistic effects on PMA-dependent gene expression, no molecular target or mechanism of synergism has been characterized yet. We now report, that RA synergistically enhances the induction of c-fos, but not c-jun mRNA by PMA in cells whose growth was stimulated by RA alone. The responding cells were hybrids of tumor cell lines whose growth and PMA-dependent c-fos mRNA expression remained unaffected by RA. The increase in PMA-dependent c-fos expression required pretreatment of cells with RA for at least 2-4 h and was achieved at doses as low as 10(-10) M. Nuclear run-on experiments and transient transfection assays using a chimeric reporter gene construct with sequences from the c-fos promoter indicated that RA did not affect PMA-dependent c-fos transcription. Instead, RA stabilized the c-fos message after induction by PMA as assessed by measuring the half-life of c-fos mRNA in actinomycin D-treated cells. This post-transcriptional regulation provides a mechanism whereby RA can synergistically enhance gene expression by PMA.
 ...
PMID:Synergistic increase of phorbol ester-induced c-fos mRNA expression by retinoic acid through stabilization of the c-fos message. 833 49

Melanoma cell invasion in vitro was tested by means of confrontation cultures of melanoma multicellular spheroids with rounded fragments of embryonic chick heart tissue. Quantitative determination of invasion was performed using a computerized image analysis program, facilitating the evaluation of the efficacy of potentially anti-invasive compounds. Retinoic acid (RA; 1 microM) [corrected] considerably impaired K1735-M2 melanoma cell invasion, as demonstrated by various measuring parameters. Parameter TUMAREA, expressing the amount of tumor tissue, indicates a growth inhibitory effect and the invasion parameter STRCSTR shows that after treatment with RA the stromal component was better preserved than in untreated controls. Besides the inhibitory effect of RA on melanoma cell invasion in confrontation cultures, RA increased the dynamics of adhesion of melanoma cells to the extracellular matrix components type I collagen and laminin, and slightly impaired melanoma cell directional migration. Fluorescence microscopy using rhodamine-labeled phalloidin showed that RA also modulated the organization of the actin cytoskeleton by inducing the formation of actin-containing stress fibers. Our data show that 1 microM RA exhibited a pronounced anti-invasive effect on highly metastatic melanoma cells in vitro. Impairment of host tissue degradation, altered adhesion abilities, changes in the actin cytoskeleton, as well as the antiproliferative effect may all account for inhibition of melanoma cell invasion.
 ...
PMID:Inhibition of K1735-M2 melanoma cell invasion in vitro by retinoic acid. 837 16

Retinoic acid (RA) induces the differentiation of tumor cells of neural origin and may do so by binding to one or more nuclear receptor proteins. We have identified transcripts and nuclear RA receptor (RAR) protein in a clonal line of human neuroblastoma cells that differentiate in response to RA. Prior to any exposure to RA, LA1-15n cells express two transcripts for RAR alpha (approximately 3.6 and approximately 2.7 kb) as well as low levels of transcript for RAR beta (approximately 3.4) and RAR gamma (approximately 2.8 kb). Exposure of LA1-15n cells to RA leads to the induction of a approximately 2.9-kb RAR beta mRNA, whereas the expression of transcripts for RARs alpha and gamma does not change appreciably. The 2.9-kb RAR beta transcript is increased by 4 h (8-fold) and continues to increase for 24-48 h (40- to 60-fold). The RA-associated increase in RAR beta mRNA in LA1-15n cells is not diminished by the addition of the protein synthesis inhibitor, cycloheximide, but is abolished by the addition of the RNA synthesis inhibitor, actinomycin D. In addition to RAR transcripts, LA1-15n cells contain a nuclear protein with the requisite characteristics of a RAR. The nuclear protein binds all-trans-[3H]RA with high affinity (Kd approximately 0.2 nM). The nuclear protein sediments at approximately 4S, which is consistent with the molecular mass deduced from RAR cDNAs (approximately 50,000 Da). The nuclear protein is clearly distinguishable from a all-trans-[3H]RA-binding protein found in the cytosolic fraction of LA1-15n cells. The cytosolic protein sediments at approximately 2S on sucrose density gradients, consistent with the expected molecular mass of the cellular retinoic acid-binding protein (approximately 16,000 Da). The nuclear [3H]RA-binding protein binds to DNA-cellulose and to the RAR beta response element. These results support the hypothesis that RARs are present in human neuroblastoma cells and may be involved in human neuroblastoma cell differentiation. They also demonstrate that RA markedly influences the expression of steady-state levels of mRNA for one of its own receptors, the RAR beta.
 ...
PMID:Identification and characterization of all-trans-retinoic acid receptor transcripts and receptor protein in human neuroblastoma cells. 838 32

Retinoids inhibit the biological effects induced in mouse epidermal cells by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Specific nuclear retinoic acid receptors (RARs) have been identified in the epidermis, but the specific receptor that mediates the inhibitory response by retinoids is not established. Retinoic acid and six conformationally restricted retinoids were evaluated in an in vitro bioassay using the JB6 mouse epidermal cell line. These activities were then compared with the ability of these retinoids to activate the RARs in transient transfection assays for transcriptional activation to identify the retinoid receptor involved in inhibiting TPA-induced anchorage-independent growth. The retinoids inhibited TPA-induced colony formation of JB6 cells in semisolid medium at concentrations that were not toxic based on colony formation of attached cells. These concentrations ranged from less than 10(-9)-10(-6) M. 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylanthracen-2-yl)benzoic acid (TTAB) was the most potent retinoid, with an EC50 of 0.8 nM. Both RAR alpha and RAR gamma were expressed in JB6 cells. Expression of RAR beta was not detected in these cells using a polymerase chain reaction assay, consistent with its extremely low level in mouse skin. Inhibition of the TPA response by these retinoids in JB6 cells correlated only with their transcriptional activation of RAR alpha, but not with that of RAR alpha. These results suggest that RAR gamma is most probably the receptor that mediates the chemopreventive effects of retinoids in mouse epidermis.
 ...
PMID:Correlation of the ability of retinoids to inhibit promoter-induced anchorage-independent growth of JB6 mouse epidermal cells with their activation of retinoic acid receptor gamma. 840 97

The oncogene jun encodes a transcription factor of the AP-1 family. In mice carrying viral jun (v-jun) as a transgene, wounding is a prerequisite for tumorigenesis, suggesting collaboration between the transgene and a wound-related event. To define possible candidates for this collaborative process, we examined the effect of several wound-related polypeptide growth factors on cells from transgenic mice. Tumor necrosis factor alpha and interleukin 1 alpha induce anchorage independence in embryo fibroblasts and tumor cell revertants from these mice. This effect was specific for the two cytokines and was restricted to cells from v-jun transgenic mice. Anchorage independence required the continued presence of the cytokines. Transfection of transgenic cells with a v-jun expression plasmid also induced anchorage independence and a tumorigenic phenotype in transgenic tumor cell revertants. However, there was no correlation between anchorage independence, expression of Jun, and AP-1 activity. These results suggest that while increased transgene expression can enhance the growth properties of v-jun transgenic cells, there exist other cytokine-dependent mechanisms that have a similar effect. Retinoic acid, dexamethasone, or forskolin inhibits induction of anchorage independence by tumor necrosis factor alpha, interleukin 1 alpha, and transfected v-jun. Although these agents affect both AP-1 transactivation potential and DNA binding in the transgenic cells, the changes are not correlated with the inhibition of growth.
 ...
PMID:Tumor necrosis factor alpha and interleukin 1 alpha induce anchorage independence in v-jun transgenic murine cells. 842 96

The effects of induced differentiation on telomerase activity were examined in human acute promyelocytic leukemic (NB4) and human embryonal carcinoma (NTERA-2) cells exposed to all-trans-retinoic acid or hexamethylene bisacetamide. Retinoic acid treatment of NB4 and NTERA-2 cells, and hexamethylene bisacetamide treatment of NTERA-2 cells caused a decline in telomerase activity in differentiation-sensitive but not in resistant clones of these cell lines. Changes in telomerase activity as measured by the PCR-based telomeric repeat amplification protocol assay were noted by 24-72 h of exposure to the inducer, suggesting that its regulation may precede terminal differentiation. The degree of telomerase activity decline was greater in NB4 cells than in NTERA-2 cells, probably reflecting in part a more mature state of NB4 cells after 5 days of exposure to the inducer. Mixing of protein extracts from treated and untreated cells did not suggest the presence of diffusible telomerase inhibitors. Expression of the RNA component of telomerase was also examined in NB4 cells, and its decline correlated with the reduced telomerase activity measured by the telomeric repeat amplification protocol assay during induced differentiation of these tumor cells. Taken together, these findings indicate that telomerase is a regulated enzyme system during induced human tumor cell differentiation, showing an inverse relationship between the degree of differentiation and telomerase activity. These models will be be useful to study the regulation and role of telomerase during induced differentiation of human tumor cells.
 ...
PMID:Telomerase activity is repressed during differentiation of maturation-sensitive but not resistant human tumor cell lines. 860 93

Retinoic acid receptors (RARs) are nuclear transcription factors that are activated by all-trans-retinoic acid or 9-cis-retinoic acid and are found in all tissues but predominantly in developing fetus, dividing tumor cells, and adult skin. Three forms of these receptors, alpha, beta, and gamma, have been described. In this paper we report the presence of RAR alpha and beta determined by hybridization with anti-sense messenger RNA, and histochemical localization of the three forms of RARs using monospecific polyclonal antibodies in various tissues of early human embryos. In a 54-day-old embryo, RAR alpha was expressed primarily in the liver and the brain, with somewhat lesser expression in the intestine. RAR beta was the highest in the brain, followed by a restricted expression in the intestine and the liver. Other organs, i.e., adrenal, kidney, and testis, did not show measurable amounts of RAR beta. The immunohistochemical localization in anterior sections of a 43-day-old embryo indicated that RAR alpha was present in the neuroepithelial cells and in cells lining the primitive pharyngeal sac, dorsal aorta, and pericardium. RAR beta was somewhat less prevalent in same tissues, whereas the expression of RAR gamma was the lowest of the three RARs in any tissues examined. Results indicated that RAR alpha and beta appear at early stages of human embryonic development and their expression is restricted to certain types of tissues.
 ...
PMID:Localization of retinoic acid receptors in anterior-human embryo. 861 22

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.
 ...
PMID:RAR beta 2-mediated growth inhibition in HeLa cells. 863 81

Retinoic acid is a known morphogen which can regulate cell proliferation and differentiation and also induces the hypophosphorylation of the RB (retinoblastoma tumor suppressor gene) protein, a known cell cycle regulatory protein. The mechanism by which these processes occur is unclear. We find that these processes can be regulated by CGP 52411, 4,5-dianilinophthalimide, an inhibitor of tyrosine protein kinases of the EGF receptor subfamily. Retinoic acid causes the largely phosphorylated RB protein expressed in proliferating HL-60 human promyelocytic leukemia cells to shift to the unphosphorylated form, as well as causing the cells to G0 arrest and differentiate. Addition of CGP 52411 accelerated the redistribution of the RB protein expressed in HL-60 cells to the unphosphorylated form, enhancing the effects of the retinoic acid. By itself CGP 52411 had no apparent effect on the RB protein expressed in HL-60 cells. CGP 52411 also accelerated the retinoic acid-induced accumulation of cells in G1/0 and the phenotypic conversion of cells to the mature myeloid phenotype, suggesting that its target is common to the regulation of both RB phosphorylation and cell proliferation and differentiation. CGP 52411 had a similar effect on the RB phosphorylation shift induced by 1,25-dihydroxy vitamin D3, a ligand for a receptor in the same steroid thyroid hormone superfamily as retinoic acid. Increasing the concentration of CGP 52411 enhanced the acceleration of RB hypophosphorylation in the case of both retinoic acid and 1,25-dihydroxy vitamin D3. The data are consistent with the negative regulation of retinoic acid induced RB protein dephosphorylation coupled to cell cycle arrest and differentiation by a receptor tyrosine kinase sensitive to CGP 52411.
 ...
PMID:Retinoic acid-induced RB (retinoblastoma) hypophosphorylation enhanced by CGP 52411 (4,5-dianilinophthalimide), an EGF family tyrosine kinase receptor inhibitor. 874 Dec 14

Retinoic acid (RA) is a multifunctional drug that is particularly effective at preventing the development of multiple primary oral squamous cell carcinomas. A portion of this activity is due to the inhibition of tumor angiogenesis. It has been thought that RA influences tumor angiogenesis only via its interactions with the tumor cells themselves. Here, we test the hypothesis that the drug can also block neovascularization by directly inhibiting the angiogenic activity of normal endothelial cells. Clinically achievable doses of RA rapidly caused large- and small-vessel endothelial cells to become refractory to stimulation of migration either by tumor-conditioned media or purified angiogenic factors (a-fibroblast growth factor (aFGF), bFGF, vascular endothelial GF, platelet-derived GF, TGF beta-1, and IL-8). However, RA had little effect on their proliferation. Inhibition of migration was complete within 3 hours and was reversed 36 hours after drug removal. The migration of human oral keratinocytes was not sensitive to RA, whereas the migration of fibroblasts and vascular smooth muscle cells was inhibited. To determine if systemic RA affected neovascularization, rats were given 1 mg/kg/day of all-trans RA and their angiogenic potential was tested by implanting pellets of tumor-conditioned media into their avascular corneas. This treatment rendered the rats unable to mount a neovascular response in their corneas. These data demonstrate that RA directly affects endothelial cells, rapidly and reversibly inhibiting their ability to migrate toward a variety of stimuli in vitro and halting the formation of new vessels in vivo. These direct effects on vascular cells seem likely to contribute to the success of RA as a chemopreventive agent for oral squamous cell carcinoma.
 ...
PMID:Inhibition of squamous cell carcinoma angiogenesis by direct interaction of retinoic acid with endothelial cells. 878 Jan 65


<< Previous 1 2 3 4 5 6 7 8 9 10