Transforming growth factor beta1 (TGF beta1) induces growth arrest in many
cell types, including B lymphocytes. We examined the effect of TGF on cell
cycle progression of a non-Hodgkin lymphoma cell line of follicular lymphom
a subtype (FL). After 48 h of TGF beta1 (10 ng/ml) treatment, a significant
ly increased number of DoHH2 cells was retained in G(0)/G(1) phase. We exam
ined the level of cell cycle components, cyclins, cyclin-dependent kinases
(cdk), and their inhibitors. We found that the expression of cyclin A and p
21(WAF1) molecules was primarily modulated by TGF beta1 treatment while the
expression of other regulatory components, like cyclins D, cyclin E, cdk2,
cdk4, and cdk6 or p15(INK4B), p16(INK4A), and p27(KIP1) was not significan
tly affected. We further examined expression and activity of CREB/ATF famil
y members to examine their roles in cyclin A inhibition. The binding activi
ty of CREB-1 and ATF-8 to the CRE region of the cyclin A promoter was almos
t completely abolished due to the treatment. The total level of CREB-1, ATF
-2, and ATF-3 was notably reduced. Moreover, CREB-1 was dephosphorylated du
e to the treatment as revealed by immunoblotting. We assume that down-regul
ation of cyclin A was mediated by the absence of CREB/ATF activation dimers
. The profound effect on the ATF family of transcription factors indicates
the complexity of TGF beta1 action on FL B malignant cells. (C) 2000 Academ
ic Press.