PMID- 9692555
OWN - NLM
STAT- MEDLINE
DCOM- 19980820
LR  - 20131121
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 16
IP  - 26
DP  - 1998 Jul 2
TI  - Specific retinoid receptors cooperate to signal growth suppression and maturation 
      of human embryonal carcinoma cells.
PG  - 3471-80
AB  - This study addresses the contributions of specific retinoid receptors during 
      all-trans-retinoic acid (RA)-mediated differentiation and growth suppression of 
      human embryonal carcinoma cells. The pleiotropic effects of RA are mediated by 
      retinoic acid receptors (RARs) and retinoid X receptors (RXRs), members of the 
      nuclear receptor family of transcription factors. After RA-treatment the 
      multipotent human embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) 
      displays limited proliferative potential, reduced tumorigenicity, and morphologic 
      and immunophenotypic neuronal maturation. RARgamma over-expression in NT2/D1 
      cells signals mesenchymal NT2/D1 terminal differentiation while RARalpha and 
      RARbeta do not and RARgamma overcomes retinoid resistance in an NT2/D1 clone 
      (NT2/D1-RI) having deregulated RARgamma expression. Since RARgamma transfectants 
      do not display neuronal maturation, this study sought to identify cooperating 
      retinoid receptors engaged in NT2/D1 differentiation. Through gain of function 
      experiments, this report highlights RXRbeta as playing an important role along 
      with RARgamma in signaling differentiation of NT2/D1 cells. Stable 
      over-expression of RXRbeta, but not RXRalpha or RXRgamma, was found to signal 
      NT2/D1 growth suppression and to induce a non-neuronal morphology and 
      immunophenotype. Notably, co-transfection of RARgamma and RXRbeta resulted in 
      marked growth suppression and for the first time, expression of typical neuronal 
      markers of NT2/D1 differentiation. To clarify the role of RXRbeta and RARgamma in 
      this differentiation program, a modified transient fibroblast growth factor-4 
      (FGF4) promoter-enhancer reporter assay that reflects effective RA-mediated 
      differentiation of NT2/D1 cells was employed. Transfection of RARgamma or RXRbeta 
      in NT2/D1 cells augments transcriptional repression of the FGF4 reporter and 
      RARgamma and RXRbeta co-transfection markedly repressed reporter activity, 
      indicating the combined role of these receptors in RA-induced NT2/D1 
      differentiation. Taken together, these findings reveal specific retinoid 
      receptors must cooperate to signal terminal growth suppression and maturation of 
      NT2/D1 cells. Since the transcriptional repression of FGF4 is coupled to the 
      effective maturation of human embryonal carcinoma cells, the described 
      co-transfection strategy should prove useful to identify genes with positive or 
      negative effects on the differentiation program of these tumor cells.
FAU - Spinella, M J
AU  - Spinella MJ
AD  - Department of Medicine, Memorial Hospital, Sloan-Kettering Institute, Memorial 
      Sloan-Kettering Cancer Center, New York, NY 10021, USA.
FAU - Kitareewan, S
AU  - Kitareewan S
FAU - Mellado, B
AU  - Mellado B
FAU - Sekula, D
AU  - Sekula D
FAU - Khoo, K S
AU  - Khoo KS
FAU - Dmitrovsky, E
AU  - Dmitrovsky E
LA  - eng
GR  - R01-CA54494-06/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (FGF4 protein, human)
RN  - 0 (Fibroblast Growth Factor 4)
RN  - 0 (Growth Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Transcription Factors)
RN  - 5688UTC01R (Tretinoin)
RN  - 62031-54-3 (Fibroblast Growth Factors)
SB  - IM
MH  - Carcinoma, Embryonal/*metabolism
MH  - Cell Differentiation
MH  - Cell Division
MH  - Dimerization
MH  - Fibroblast Growth Factor 4
MH  - Fibroblast Growth Factors/biosynthesis/genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Genes, Reporter
MH  - Growth Inhibitors
MH  - Humans
MH  - Proto-Oncogene Proteins/biosynthesis/genetics
MH  - Receptors, Retinoic Acid/genetics/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Retinoid X Receptors
MH  - Signal Transduction
MH  - Transcription Factors/genetics/metabolism
MH  - Tretinoin/*pharmacology
EDAT- 1998/08/06 00:00
MHDA- 1998/08/06 00:01
CRDT- 1998/08/06 00:00
PHST- 1998/08/06 00:00 [pubmed]
PHST- 1998/08/06 00:01 [medline]
PHST- 1998/08/06 00:00 [entrez]
AID - 10.1038/sj.onc.1201876 [doi]
PST - ppublish
SO  - Oncogene. 1998 Jul 2;16(26):3471-80. doi: 10.1038/sj.onc.1201876.