Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3–dependent signal transduction by phosphorylating human retinoid X receptor α

(8), and other cellular and physiological processes. Many of the actions of 1,25-D are mediated by an intracellular receptor, the vitamin D receptor (VDR), a member of the steroid/thyroid receptor superfamily of ligandregulated transcription factors (9, 10). The activity of VDR is dependent not only on the concentration of receptor and hormone but also on its heterodimer partner, retinoid X receptor (RXR), and the coactivator proteins that bind to the VDR and facilitate transcription of target genes (11).In addition to its actions as a modulator of transcription through activation of the VDR, 1,25-D can rapidly activate cell signaling cascades independent of a requirement for transcription (12-14). The means by which 1,25-D induces these changes has not been fully elucidated. Rapid activation of extracellular signal-regulated kinases, ERK1/ERK2 in NB4 promyelocytic leukemia cells can be induced not only by 1,25-D, but also by analogs that are unable to activate VDR, suggesting the possibility of a separate receptor (15). Antibodies to a membrane protein identified by Nemere et al. (16) block the ability of 1,25-D to induce rapid calcium uptake and activation of PKC in cartilage cells. VDRϪ/Ϫ osteoblasts take up calcium and activate PKC similar to the wild-type osteoblasts, implicating proteins other than VDR in these actions (17). In contrast, Gniadecki (18) has described activation of ERK through 1,25-D-induced activation of Raf as a result of interactions between VDR and the adaptor protein Shc. VDR-null osteoblasts do not exhibit ion channel responses in response to 1,25-D (13) and Erben et al. (14) have reported that deletion of the VDR DNA binding domain also eliminates non-genomic responses. Thus some of the rapid actions of 1,25-D may be dependent upon VDR, whereas others are not.Nuclear receptor family members including VDR and RXR as well as many of their coactivators, are phosphoproteins whose activities are also regulated by cell signaling pathways (19 -27). Thus 1,25-D can modulate VDR activity both through direct binding to VDR as well as by altering the kinase activities within the cell (9,11,12,28). Although VDR has not been reported to be a substrate for ERK, RXR␣ (one of the three RXR isoforms) (29) is phosphorylated by ERK, as are some of the VDR coactivators including SRC-1 (30).To better understand the functional interactions between VDR and the ERK signaling pathway, we sought to determine whether 1,25-D activates ERK in the osteoblastic cell lines, MG-63 and MC3T3-E1, and to evaluate the effects of ERK on VDR activity. We found that 1,25-D rapidly induced ERK activity and that this activation persisted at 24 h in both cell lines. Surprisingly, the effects of ERK activation on VDR activity in the two cell lines were very different. Overexpression of Raf-1 (an upstream activator of ERK) reduced VDR activity in MC3T3-E1 cells, but stimulated activity in MG-63 cells.

Section: Differential Regulation Of Vdr Activity In Mc3t3-e1 Cells Ismentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

The Functional Consequences of Cross-talk between the Vitamin D Receptor and ERK Signaling Pathways Are Cell-specific

Narayanan

Sepúlveda

Falzon

et al. 2004

“…The presence of nuclear localization signals on adipogenic transcription factors have been described in some detail for C/EBP (56) and CREB (57), and they have been inferred from large deletions for PGC-1␣ (58) and a mutation forming a truncated PPAR␣ (59); however, there have been no reports indicating that a change in nuclear localization is a mechanism for regulating adipogenesis. In addition, phosphorylation is a common mechanism associated with the regulation of nuclear translocation, and although phosphorylation occurs on adipogenic transcription factors (58,60,61), the function of phosphorylation in the control of adipogenesis is not well understood (62), nor has it been previously associated with mechanisms of nuclear translocation.…”

Section: Fig 7 Nuclear Translocation Of Pka and Nf-bmentioning

confidence: 99%

Sequestration of Thermogenic Transcription Factors in the Cytoplasm during Development of Brown Adipose Tissue

Rim

Xue

Gawrońska‐Kozak

et al. 2004

Transcription factors that regulate gene expression during adipogenesis also control the expression of genes of thermogenesis in brown adipose tissue, in particular, the mitochondrial uncoupling protein gene (Ucp1). There is evidence that a plasticity exists among adipocytes in which activation of the Ucp1 gene together with mitochondrial biogenesis can increase the brown adipocyte character of white fat. To understand this process, we have characterized the changes in transcription that occur in interscapular brown adipocytes during development. We have found dramatic reductions in both DNA-binding activity to probes and immunoreactive protein for peroxisome proliferator-activated receptor, retinoid X receptor, CCAAT/enhancer binding protein, and cAMP-response element-binding protein regulatory motifs in nuclear extracts when mice reach adulthood. Exposure of adult mice to the cold, which reactivates Ucp1 expression, leads to a re-accumulation of factors in the nucleus. We propose that transcription factors are sequestered in the cytoplasm as mice age under conditions of reduced thermogenesis. Changes in isoform subtypes for peroxisome proliferator-activated receptor-␥ and cAMP-response element-binding proteins indicate an additional level of control on gene expression during thermogenesis. The increased movement of the RII␤ protein kinase A regulatory subunit into the nucleus with age suggests a mechanism for regulating the phosphorylation of transcription factors in the nucleus in response to the thermogenic requirements of the animal. Nuclear factor-B has been used as a model to demonstrate that the nuclear localization of transcription factors in brown fat are reduced during post-natal development. Furthermore, it was found by immunofluorescence that adrenergic stimulation of primary adipocyte cultures causes an increase of both the protein kinase A catalytic ␣-subunit and nuclear factor-B into the nucleus.

“…2a). Phosphorylation of RXRs in response to the activation of various pathways by extracellular stimuli has been described before (27)(28)(29). However, the phosphorylation of RXR and the interaction between a protein kinase and RXR that is induced by RXR agonist have never been reported.…”

Section: Rxr Agonist Induces Growth Inhibition and Apoptosis In Cellsmentioning

confidence: 99%

Casein Kinase 1α Interacts with Retinoid X Receptor and Interferes with Agonist-induced Apoptosis

Zhao¹,

Qin²,

Atangan³

et al. 2004

Agonists of retinoid X receptors (RXRs), which include the natural 9-cis-retinoic acid and synthetic analogs, are potent inducers of growth arrest and apoptosis in some cancer cells. As such, they are being used in clinical trials for the treatment and prevention of solid tumors and are used to treat cutaneous T cell lymphoma. However, the molecular mechanisms that underlie the anticancer effects of RXR agonists remain unclear. Here, we show that a novel pro-apoptotic pathway that is induced by RXR agonist is negatively regulated by casein kinase 1␣ (CK1␣). CK1␣ associates with RXR in an agonist-dependent manner and phosphorylates RXR. The ability of an RXR agonist to recruit CK1␣ to a complex with RXR in cells correlates inversely with its ability to inhibit growth. Remarkably, depletion of CK1␣ in resistant cells renders them susceptible to RXR agonist-induced growth inhibition and apoptosis. Our study shows that CK1␣ can promote cell survival by interfering with RXR agonist-induced apoptosis. Inhibition of CK1␣ may enhance the anti-cancer effects of RXR agonists.