Transforming growth factor-beta 1 down-regulation of major histocompatibility complex class I in thyrocytes: Coordinate regulation of two separate elements by thyroid-specific as well as ubiquitous transcription factors
G. Napolitano et al., Transforming growth factor-beta 1 down-regulation of major histocompatibility complex class I in thyrocytes: Coordinate regulation of two separate elements by thyroid-specific as well as ubiquitous transcription factors, MOL ENDOCR, 14(4), 2000, pp. 486-505
Transforming growth factor (TGF)-beta 1-decreased major histocompatibility
complex (MHC) class I gene expression in thyrocytes is transcriptional; it
involves trans factors and cis elements important for hormone- as well as i
odide-regulated thyroid growth and function. Thus, in rat FRTL-5 thyrocytes
, TGF-beta 1 regulates two elements within -203 bp of the transcription sta
rt site of the MHC class I 5'-flanking region: Enhancer A, -180 to -170 bp,
and a downstream regulatory element (DRE), -129 to -90 bp, that contains a
cAMP response element (CRE)-like sequence. TGF-beta 1 reduces the interact
ion of a NF-kappa B p50/fra-2 heterodimer (MOD-1) with Enhancer A while inc
reasing its interaction with a NF-kappa B p50/p65 heterodimer. Both reduced
MOD-1 and increased p50/p65 suppresses class I expression. Decreased MOD-1
and increased p50/p65 have been separately associated with the ability of
autoregulatory (high) concentrations of iodide to suppress thyrocyte growth
and function, as well as MHC class I expression. TGF-beta 1 has two effect
s on the downstream regulatory element (DRE). It increases DRE binding of a
ubiquitously expressed Y-box protein, termed TSEP-1 (TSHR suppressor eleme
nt binding protein-1) in rat thyroid cells; TSEP-1 has been shown separatel
y to be an important suppressor of the TSH receptor (TSHR) in addition to M
HC class I and class II expression. It also decreases the binding of a thyr
oid-specific trans factor, thyroid transcription factor-1 (TTF-l), to the D
RE, reflecting the ability of TGF-beta 1 to decrease TTF-1 RNA levels. TGF-
beta 1-decreased TTF-l expression accounts in part for TGF-beta 1-decreased
thyroid growth and function, since decreased TTF-l has been shown to decre
ase thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR gene
expression, coincident with decreased MHC class I. Finally, we show that TG
F-beta 1 increases c-jun RNA levels and induces the formation of new comple
xes involving c-jun, fra-2, ATF-1, and c-fos, which react with Enhancer A a
nd the DRE. TGF-beta 1 effects on c-jun may be a pivotal fulcrum in the hit
herto unrecognized coordinate regulation of Enhancer A and the DRE.