Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P19793 (retinoid X receptor alpha)
 391 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human retinoid X receptor alpha (hRXR alpha) is a member of the nuclear receptor family of transcriptional regulators. It regulates transcription through its association with several heterodimeric partners, including the vitamin D3 receptor (VDR). Signaling through the VDR is essential for normal calcium homeostasis and has been shown to inhibit the proliferation of cancer cells derived from a number of tissues. Here we show that phosphorylation of hRXR alpha in ras-transformed human keratinocytes through the activated Ras-Raf-mitogen-activated protein kinase (Ras-Raf-MAP kinase) pathway results in attenuated transactivation by the VDR and resistance to the growth inhibitory action of 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] and RXR-specific agonist LG1069 (4-[1-(5,6,7, 8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl]-benzoic acid). Phosphorylation of hRXR alpha occurs at serine 260, a consensus MAP kinase site. Inhibition of MAP kinase activity or point mutagenesis of serine 260 of hRXR alpha reverses the observed resistance to 1,25(OH)2D3 and LG1069. Thus, hRXR alpha is a downstream target of MAP kinase, and its phosphorylation may play an important role in malignant transformation.
 ...
PMID:Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor alpha. 1037 79

We have previously reported that the activation of resting human immature peripheral blood T (PBT) lymphocytes is associated with the loss of retinoid X receptor alpha (RXRalpha) expression. In the present study, we have demonstrated that, unlike resting cells, activation of cycling human mature PBT lymphocytes, and T lymphocyte leukemia cell lines is accompanied by the accumulation of RXRalpha mRNA and protein. Interestingly, cyclosporin A further augmented RXRalpha expression, indicating the involvement of calcineurin pathways in the process. 9-cis retinoic acid inhibited the accumulation, suggesting that retinoids can regulate the synthesis of their own receptors during T cell activation. Transfection analysis in Jurkat cells, using RXRE-dependent reporter assays, showed that RXRalpha accumulated during T cell activation was transcriptionally inactive. To investigate the mechanism of such inhibition, the role of two mitogen-activated protein kinase pathways, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), in modulating RXRE-dependent transcription, was explored. The expression of constitutively active MAP/ERK kinase kinase 1 (MEKK1) inhibited RXRE-dependent transcription, whereas dominant negative MEKK1 increased the transcription, indicating the involvement of JNK signaling pathways in the process. In contrast, expression of constitutively active MEK1, which activates ERK pathway, enhanced RXRE-dependent activation. When both were activated simultaneously, JNK pathway was dominant over ERK pathway and resulted in inhibition of RXRE-mediated transcription. These data demonstrate a dual regulatory control of RXRalpha expression during the activation of resting and cycling T lymphocytes and indicate a dynamic balance between JNK and ERK pathways in modulating RXRE-mediated transactivation.
 ...
PMID:Accumulation of RXR alpha during activation of cycling human T lymphocytes: modulation of RXRE transactivation function by mitogen-activated protein kinase pathways. 1103 54

Human retinoid X receptor alpha (hRXRalpha) plays a critical role in DNA binding and transcriptional activity through its heterodimeric association with several members of the nuclear receptor superfamily, including the vitamin D receptor (VDR). Several cancer cell lines derived from different tissues have been shown to be resistant to the growth-inhibitory action of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active metabolite of vitamin D(3). Here we show that in RAS-transformed keratinocytes, Ser260 of hRXRalpha is phosphorylated through the RAS-RAF-MAP kinase cascade. This phosphorylation event results in the inhibition of vitamin D signaling via VDR/hRXRalpha heterodimers. Strategies to reverse this resistance include the use of the MAP kinase inhibitor, PD098059, and a non-phosphorylatable hRXRalpha mutant, Ala260, which completely abolishes RXR phosphorylation and restores the function of both 1,25(OH)(2)D(3) and a specific RXR ligand, LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl)ethenyl]-benzoic acid). In addition, we show that a vitamin D analog with low calcemic activity (EB1089) is more potent than 1,25(OH)(2)D(3) in inhibiting cancer cell growth in this system. Targeted therapy with selective analogs such as EB1089, in combination with the inhibition of phosphorylation of the RXR, could play a critical role in the development of strategies for cancer treatment.
 ...
PMID:Vitamin D resistance in RAS-transformed keratinocytes: mechanism and reversal strategies. 1112 Dec 28

Vitamin D, parathyroid hormone (PTH), and parathyroid hormone-related peptide (PTHrP) are major regulators of calcium metabolism and vitamin D can also reduce the growth of normal cells and tumor cells. PTHrP and PTH act via a common membrane receptor (PTHR). The mouse PTHR is regulated by a kidney-selective upstream promoter P(1) and ubiquitous downstream promoter P(2). In vitro and in vivo 1,25(OH)(2)D can inhibit PTHR expression in bone but not cartilage by downregulating transcription via P(2). Gene transcription of PTHrP per se can also be downregulated by 1,25(OH)(2)D and by low calcemic vitamin D analogs. This inhibitory effect may reduce the hypercalcemia caused by overproduction of PTHrP by tumor cells. In a malignant keratinoctye cell line, phosphorylation of the retinoid X receptor alpha occurs through the activated Ras-MAP kinase pathway and results in attenuated trans-activation by the vitamin D receptor, its heterodimeric partner. This decreases the growth-inhibitory efficacy of 1,25(OH)(2)D. Studies of the capacity of vitamin D to alter PTHrP production and action and of its anti-proliferative effects can, therefore, shed important light on basic mechanisms controlling these events, and may also have major implications for clinical medicine and therapeutics.
 ...
PMID:Studies of the effects of 1,25-dihydroxyvitamin D on skeletal and calcium homeostasis and on inhibition of tumor cell growth. 1138 62

Retinoids induce apoptosis and differentiation of hepatocellular carcinoma (HCC) cells and are used clinically in the chemoprevention of HCC. We have shown previously that hepatocarcinogenesis is accompanied by accumulation of full-length retinoid X receptor alpha (RXRalpha), although the underlying mechanisms and biological implications have remained unclear. The present studies were based on the finding that the accumulated full-length RXRalpha was phosphorylated at serine/threonine residues both in all human HCC tissues examined and in human HCC-derived HuH7 cells. Phosphorylation at serine 260 of RXRalpha, a consensus site of mitogen-activated protein kinase, was closely linked to its retarded degradation, low transactivating activity, and the promotion of cancer cell growth. There was no genomic mutation in the RXRalpha gene, and abrogation of phosphorylation by mitogen-activated protein kinase-specific inhibitors restored the degradation of RXRalpha in an RXR ligand-dependent manner. These results suggest that phosphorylation of RXRalpha may interfere with its metabolism and signaling in human HCC, which could lead to growth promotion of these tumors.
 ...
PMID:Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma. 1160 11

Retinoid X receptor alpha (RXRalpha) has emerged as an important nuclear receptor involved in hepatocarcinogenesis, because its ligand suppresses the development of hepatocellular carcinoma (HCC) in both experimental and clinical studies. We have demonstrated that phosphorylation of RXRalpha at serine 260 interferes with its function and delays its degradation in cultured human HCC, leading to enhanced cellular proliferation. Here, we show that in normal liver and in nonproliferating hepatocyte cultures, RXRalpha is unphosphorylated and highly ubiquitinated, rendering it sensitive to proteasome-mediated degradation. On the other hand, phosphoserine 260 RXRalpha is resistant to ubiquitination and proteasome-mediated degradation in both human HCC tissues and a human HCC cell line, HuH7. In these tissues and cells, serine 260 is phosphorylated by mitogen-activated protein (MAP) kinase. In proliferating normal hepatocytes, similar to HCC cells, RXRalpha is also phosphorylated at serine 260 and resistant to ubiquitin-mediated degradation by proteasome, but this ubiquitination of RXRalpha is differentially regulated between HCC cells and normal hepatocytes. In proliferating hepatocytes, 9-cis retinoic acid (9cRA), a ligand to RXRalpha, suppresses MAP kinase-mediated phosphorylation and thereby enhances ubiquitination of RXRalpha, whereas it fails to exert these effects in HCC cells. In conclusion, switching of the ubiquitin/proteasome-dependent degradation of RXRalpha by phosphorylation at serine 260 may be responsible for the aberrant growth of HCC and its suppression by retinoids.
 ...
PMID:Phosphorylation of retinoid X receptor suppresses its ubiquitination in human hepatocellular carcinoma. 1182 6

The current study investigated the action of 1,25-dihydroxyvitamin D(3) (1,25D) at the genomic and signal transduction levels to induce rat cytochrome P450C24 (CYP24) gene expression. A rat CYP24 promoter containing two vitamin D response elements and an Ets-1 binding site was used to characterize the mechanism of actions for the 1,25D secosteroid hormone. The Ets-1 binding site was determined to function cooperatively with the most proximal vitamin D response element in a hormone-dependent fashion. Evidence was obtained for distinct roles of ERK1/ERK2 and ERK5 in the 1,25D-inductive actions. Specifically, 1,25D stimulated the activities of ERK1/ERK2 and ERK5 in a Ras-dependent manner. Promoter induction was inhibited by mitogen-activated protein (MAP) kinase inhibitors (PD98059 and U0126) and a dominant-negative Ras mutant (Ras17N). Induction of CYP24 by 1,25D was also inhibited by overexpression of dominant-negative mutants of ERK1 and MEK5 (ERK1K71R and MEK5(A)). The p38 and JNK MAP kinases were not required for the action of 1,25D. 9-cis retinoid X receptor alpha (RXR alpha) interacted with ERK2 but not ERK5 in intact cells, whereas Ets-1 interacted preferentially with ERK5. Increased phosphorylation of RXR alpha and Ets-1 was detected in response to 1,25D. Activated ERK2 and ERK5 specifically phosphorylated RXR alpha and Ets-1, respectively. Mutagenesis of Ets-1 (T38A) reduced CYP24 promoter activity to levels observed with the dominant-negative MEK5(A) and inhibited ERK5-directed phosphorylation. Mutated RXR alpha (S260A) inhibited 1,25D-induced CYP24 promoter activity and abolished phosphorylation by activated ERK2. The 1,25D-inductive action through ERK5 involved Ets-1 phosphorylation at threonine 38, whereas hormone stimulation of ERK1/ERK2 required RXR alpha phosphorylation on serine 260. The ERK1/ERK2 and ERK5 modules provide a novel mechanism for linking the rapid signal transduction and slower transcription actions of 1,25D to induce CYP24 gene expression.
 ...
PMID:Role of MAP kinases in the 1,25-dihydroxyvitamin D3-induced transactivation of the rat cytochrome P450C24 (CYP24) promoter. Specific functions for ERK1/ERK2 and ERK5. 1204 11

We have reported previously that acyclic retinoid, a synthetic retinoid X receptor alpha (RXRalpha)-ligand, suppresses the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. On the other hand, HCCs become refractory to physiological concentrations of the natural RXRalpha-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXRalpha. Here, we show that acyclic retinoid restores the function of RXRalpha in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXRalpha. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXRalpha phosphorylation. Although 9cRA also suppressed Ras activity, it simultaneously down-regulated mitogen-activated protein kinase phosphatase-1, an enzyme that inactivates Erk, thereby leaving the phosphorylation status of Erk unchanged. A combination of 9cRA (a potent ligand) and acyclic retinoid (a weak ligand preventing phosphorylation) resulted in a marked cooperation in transactivation via the RXR-response element and in inhibiting the proliferation of HuH7 cells. These events provide a novel molecular basis for the antitumor activity of acyclic retinoid against HCC.
 ...
PMID:Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. 1280 34

We here review therapeutic application of a synthetic analog of retinoids (vitamin A and its derivatives), named acyclic retinoid (AR), towards chemoprevention of hepatocellular carcinoma (HCC), and its underlying molecular mechanisms. A high incidence of post-therapeutic recurrence has become a major determinant of the prognosis of HCC, especially in the patients of hepatitis virus-infected cirrhosis. Oral supplementation of AR successfully prevented the recurrence of HCC, associated with a disappearance in serum levels of lectin-reactive alpha-fetoprotein (AFP-L3), a marker of occult cancer clones in the liver, suggesting eradication of latent malignant clones from patients' liver. This led us a novel concept of 'clonal deletion' with AR as an agent that is conceptually similar to cancer chemotherapy. HCC in cirrhotic patients contains lower levels of endogenous retinoids and simultaneously is insensitive to retinoic acid (RA) because of malfunction of its nuclear receptor, retinoid X receptor alpha (RXRalpha). In HCC tissues, RXRalpha is constitutively phosphorylated by the action of extracellular signal-regulated kinase (Erk), thereby losing its transactivation activity and becoming resistant to degradation via ubiquitin/proteasome pathway. This leads to accumulation of phospho-inactivated RXRalpha, that functions as a dominant negative receptor and interferes with transactivation by remaining normal RXRalpha. AR but not natural RA prevents phosphorylation of RXRalpha and restores the function of RXRalpha via down-regulating Ras/Erk system, making HCC cells sensitive to the endogenous ligand, 9-cis-RA. This may link to both caspase-dependent and -independent apoptosis of the cancer cells via induction of growth suppressor(s) such as p21CIP1 and/or apoptosis inducer(s) including tissue transglutaminase. AR also enhances the sensitivity of HCC cells to interferons-alpha and -beta, and thereby indirectly promotes apoptosis induced by these interferons. In summary, our clinical experience and basic research together provide a strong rationale to use AR in the chemoprevention of HCC.
 ...
PMID:Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review). 1501 Aug 15

We have previously published that 2 proven treatments for acute promyelocytic leukemia, As2O3 and retinoic acid, can be antagonistic in vitro. We now report that As2O3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor alpha (RXRalpha). As2O3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRalpha. We further show that As2O3 inhibits expression of several target genes of RXRalpha partners. Phosphorylation of RXRalpha has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As2O3 phosphorylated RXRalpha in the N-terminal ABC region exclusively on serine residues. Consistent with our previous data implying a role for JNK in As2O3-induced apoptosis, we show that pharmacologic or genetic inhibition of JNK activation decreased As2O3-induced RXRalpha phosphorylation and blocked the effects of As2O3 on RXRalpha-mediated transcription. A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRalpha-mediated transcription. These data may provide some insight into the rational development of chemotherapeutic combinations involving As2O3 as well as into molecular mechanisms of arsenic-induced carcinogenesis resulting from environmental exposure.
 ...
PMID:Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation. 1618 97


1 2 Next >>