PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) disrupts normal PAX8 or PPARgamma transcriptional function and stimulates follicular thyroid cell growth.
Follicular thyroid carcinomas are associated with a chromosomal translocation that fuses the thyroid-specific transcription factor paired box gene 8 (PAX8) with the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). This study investigated the transcriptional mechanisms by which PAX8-PPARgamma regulates follicular thyroid cells. In HeLa cells, rat follicular thyroid (FRTL-5) cells, or immortalized human thyroid cells, PAX8-PPARgamma stimulated transcription from PAX8-responsive thyroperoxidase and sodium-iodide symporter promoters in a manner at least comparable with wild-type PAX8. In contrast, PAX8-PPARgamma failed to stimulate transcription from the thyroglobulin promoter and blocked the synergistic stimulation of this promoter by wild-type PAX8 and thyroid transcription factor-1. Unexpectedly, PAX8-PPARgamma transcriptional function on a PPARgamma-responsive promoter was cell-type dependent; in HeLa cells, PAX8-PPARgamma dominantly inhibited expression of the PPARgamma-responsive promoter, whereas in FRTL-5 and immortalized human thyroid cells PAX8-PPARgamma stimulated this promoter. In gel shift analyses, PAX8-PPARgamma bound a PPARgamma-response element suggesting that its transcriptional function is mediated via direct DNA contact. A biological model of PAX8-PPARgamma function in follicular thyroid cells was generated via constitutive expression of the fusion protein in FRTL-5 cells. In this model, PAX8-PPARgamma expression was associated with enhanced growth as assessed by soft agar assays and thymidine uptake. Therefore, PAX8-PPARgamma disrupts normal transcriptional regulation by stimulating some genes and inhibiting others, the net effect of which may mediate follicular thyroid cell growth and loss of differentiation that ultimately leads to carcinogenesis.
Au
Amy Y M
AY
Cancer Genetics Unit, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia.
McBride
Claire
C
Wilhelm
Kenneth G
KG
Koenig
Ronald J
RJ
Speller
Bridget
B
Cheung
Linda
L
Messina
Marinella
M
Wentworth
John
J
Tasevski
Vitomir
V
Learoyd
Diana
D
Robinson
Bruce G
BG
Clifton-Bligh
Roderick J
RJ
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D000072636:PAX8 Transcription Factor; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology* / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D047495:PPAR gamma; D051761:Paired Box Transcription Factors; D004247:DNA; D013936:Thymidine