PMID- 10377179
OWN - NLM
STAT- MEDLINE
DCOM- 19990707
LR  - 20181201
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 103
IP  - 12
DP  - 1999 Jun
TI  - Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3-dependent
      signal transduction by phosphorylating human retinoid X receptor alpha.
PG  - 1729-35
AB  - 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.
FAU - Solomon, C
AU  - Solomon C
AD  - Department of Medicine, Royal Victoria Hospital, Montreal, Quebec, Canada.
FAU - White, J H
AU  - White JH
FAU - Kremer, R
AU  - Kremer R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Anticarcinogenic Agents)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Tetrahydronaphthalenes)
RN  - 0 (Transcription Factors)
RN  - 452VLY9402 (Serine)
RN  - A61RXM4375 (Bexarotene)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - FXC9231JVH (Calcitriol)
SB  - AIM
SB  - IM
MH  - Animals
MH  - Anticarcinogenic Agents/pharmacology
MH  - Bexarotene
MH  - COS Cells
MH  - Calcitriol/*antagonists & inhibitors/metabolism/pharmacology
MH  - Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors/*physiology
MH  - Cell Line, Transformed
MH  - Cell Transformation, Neoplastic/drug effects/metabolism
MH  - Drug Resistance, Neoplasm
MH  - Genes, ras/physiology
MH  - Humans
MH  - Keratinocytes/drug effects/enzymology/metabolism
MH  - Mutagenesis, Site-Directed
MH  - Phenotype
MH  - Phosphorylation/drug effects
MH  - Receptors, Calcitriol/metabolism
MH  - Receptors, Retinoic Acid/*metabolism
MH  - Retinoid X Receptors
MH  - Serine/genetics/metabolism
MH  - *Signal Transduction/drug effects
MH  - Tetrahydronaphthalenes/pharmacology
MH  - Transcription Factors/*metabolism
MH  - Transfection
MH  - Tumor Cells, Cultured
PMC - PMC408392
EDAT- 1999/06/22 00:00
MHDA- 1999/06/22 00:01
CRDT- 1999/06/22 00:00
PHST- 1999/06/22 00:00 [pubmed]
PHST- 1999/06/22 00:01 [medline]
PHST- 1999/06/22 00:00 [entrez]
AID - 10.1172/JCI6871 [doi]
PST - ppublish
SO  - J Clin Invest. 1999 Jun;103(12):1729-35. doi: 10.1172/JCI6871.