A. Alevizopoulos et al., A PROLINE-RICH TGF-BETA-RESPONSIVE TRANSCRIPTIONAL ACTIVATOR INTERACTS WITH HISTONE H3, Genes & development, 9(24), 1995, pp. 3051-3066
The molecular mechanisms involved in the regulation of gene expression
by transforming growth factor-beta (TGF-beta) have been analyzed. We
show that TGF-beta specifically induces the activity of the proline-ri
ch trans-activation domain of CTF-1, a member of the CTF/NP-I family o
f transcription factors. A TGF-beta-responsive domain (TRD) in the pro
line-rich transcriptional activation sequence of CTF-1 was shown to me
diate TGF-beta induction in NIH-3T3 cells. Mutagenesis studies indicat
ed that this domain is not the primary target of regulatory phosphoryl
ations, suggesting that the growth factor may regulate a CTF-1-interac
ting protein. A two-hybrid screening assay identified a nucleosome com
ponent, histone H3, as a specific CTP-1-interacting protein in yeast.
furthermore, the CTF-1 trans-activation domain was shown to interact w
ith histone H3 in both transiently and stably transfected mammalian ce
lls. This interaction requires the TRD, and it appears to be upregulat
ed by TGF-beta in vivo. Moreover, point mutations in the TRD that inhi
bit TGF-beta induction also reduce interaction with histone H3. In vit
ro, the trans-activation domain of CTF-1 specifically contacts histone
H3 and oligomers of histones H3 and H4, and full-length CTF-1 was sho
wn to alter the interaction of reconstituted nucleosomal cores with DN
A. Thus, the growth factor-regulated trans-activation domain of CTF-1
can interact with chromatin components through histone H3, These findi
ngs suggest that such interactions may regulate chromatin dynamics in
response to growth factor signaling.