PMID- 8923461
OWN - NLM
STAT- MEDLINE
DCOM- 19970306
LR  - 20131121
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 10
IP  - 11
DP  - 1996 Nov
TI  - Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose 
      stromal cells through use of an activating protein-1 binding site upstream of 
      promoter 1.4.
PG  - 1350-7
AB  - Expression of aromatase P450 (P450arom; the product of the CYP19 gene) in human 
      adipose stromal cells in primary culture is markedly stimulated by serum in the 
      presence of dexamethasone (DEX). Under these conditions, the majority of P450arom 
      transcripts contain untranslated exon 1.4 at their 5'-ends. Previously, we 
      observed that the region of the CYP19 gene upstream of exon 1.4 contains a 
      TATA-less promoter, a glucocorticoid response element, and an 
      interferon-gamma-activating sequence. These act to mediate the action of 
      interleukin-6 and related cytokines to stimulate aromatase expression in the 
      presence of DEX. In the present study, we found that tumor necrosis factor-alpha 
      (TNF alpha) also acts synergistically with DEX to stimulate aromatase expression 
      in adipose stromal cells in serum-free medium. We observed that the action of TNF 
      alpha can be mimicked by ceramide. Maximal aromatase activity was obtained when 
      cells were incubated with 5 ng/ml TNF alpha or 100 nM ceramide in the presence of 
      250 nM DEX. Levels of c-fos and c-jun proteins also were increased by TNF alpha 
      or ceramide in the presence of DEX. Upstream of the interferon-gamma-activating 
      sequence site there is an imperfect activating protein-1 (AP-1) binding site 
      (2-bp mismatch). Gel retardation analysis using nucleotide probes containing the 
      putative AP-1-binding sequence and nuclear extracts of human adipose stromal 
      cells cultured in the presence of TNF alpha or ceramide plus DEX revealed that 
      adipose stromal cells nuclear proteins bind to this site and that binding was 
      competed by a 100-fold excess of a consensus AP-1 sequence. In addition, binding 
      activity was competed by both anti-c-fos and anti-c-jun sera. Mutation or 
      deletion of the putative AP-1 element resulted in the loss of TNF alpha- plus 
      DEX-induced activity of reporter constructs comprised of 515 bp of the exon 1.4 
      flanking sequence linked to the luciferase gene. These results suggest that TNF 
      alpha, probably acting through ceramide formation, stimulates the binding of both 
      c-fos and c-jun to the AP-1 element upstream of exon 1.4. These act cooperatively 
      with the ligand-activated glucocorticoid receptor to induce aromatase expression 
      in adipose stromal cells in primary culture. We conclude that this TNF alpha 
      signal transduction pathway may play an important role in the regulation of 
      estrogen biosynthesis in adipose tissue.
FAU - Zhao, Y
AU  - Zhao Y
AD  - Department of Obstetrics/Gynecology, University of Texas Southwestern Medical 
      Center, Dallas 75235, USA.
FAU - Nichols, J E
AU  - Nichols JE
FAU - Valdez, R
AU  - Valdez R
FAU - Mendelson, C R
AU  - Mendelson CR
FAU - Simpson, E R
AU  - Simpson ER
LA  - eng
GR  - R37-AG-08174/AG/NIA 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  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (Ceramides)
RN  - 0 (Glucocorticoids)
RN  - 0 (Proto-Oncogene Proteins c-fos)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 1.14.14.1 (Aromatase)
SB  - IM
MH  - Adipose Tissue/*cytology/drug effects
MH  - Administration, Topical
MH  - Anti-Inflammatory Agents/pharmacology
MH  - Antineoplastic Agents, Hormonal/pharmacology
MH  - Aromatase/drug effects/*genetics
MH  - Binding Sites
MH  - Cells, Cultured
MH  - Ceramides/pharmacology
MH  - Dexamethasone/pharmacology
MH  - Drug Synergism
MH  - Female
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Genes, Reporter
MH  - Glucocorticoids
MH  - Humans
MH  - Luciferases/drug effects/genetics
MH  - Promoter Regions, Genetic
MH  - Protein Biosynthesis
MH  - Proto-Oncogene Proteins c-fos/drug effects/genetics/metabolism
MH  - Proto-Oncogene Proteins c-jun/drug effects/genetics/metabolism
MH  - Recombinant Proteins/genetics/metabolism
MH  - Stromal Cells/drug effects/*enzymology
MH  - Transcription Factor AP-1/genetics/*metabolism
MH  - Transcription, Genetic/drug effects
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 1996/11/01 00:00
MHDA- 1996/11/01 00:01
CRDT- 1996/11/01 00:00
PHST- 1996/11/01 00:00 [pubmed]
PHST- 1996/11/01 00:01 [medline]
PHST- 1996/11/01 00:00 [entrez]
AID - 10.1210/mend.10.11.8923461 [doi]
PST - ppublish
SO  - Mol Endocrinol. 1996 Nov;10(11):1350-7. doi: 10.1210/mend.10.11.8923461.