Smad3 Potentiates Transforming Growth Factor β (TGFβ)-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes

Abstract

Transforming growth factor-␤ (TGF␤) is a potent growth inhibitor and inducer of apoptosis in B lympho

The effect of FK506 on transforming growth factor signaling and apoptosis in chronic lymphocytic leukemia B cells

“…At the same time, there was an increase in levels of death-associated protein kinase, which is a target of transcriptional activation by Smad. 16 In accordance with reports that Bim is activated and functions as an important initiator of TGF-β-induced apoptosis in both a human gastric carcinoma cell line 26 and a B-cell line, 28 Bim was upregulated in CLL cells cultured with FK506. Bmf is another BH3-only protein implicated in TGF-β-induced apoptosis 27 which plays a role in regulating the growth and survival of B cells 28 and CLL cells.…”

“…We also evaluated the expression levels of the anti-apoptotic Bcl-2 and Bcl-xL, and the pro-apoptotic BH3-only molecules, Bim and Bmf, which are implicated in commitment to TGF-β-induced apoptosis. [26][27][28] We found that the appearance of death-associated protein kinase was accompanied by a decrease of Bcl-2 and Bcl-xL and an increase of Bim ( Figure 5A). Bim is an essential regulator of lymphoid system homeostasis and appears to be essential for induction of Bcell apoptosis.…”

“…Bim is an essential regulator of lymphoid system homeostasis and appears to be essential for induction of Bcell apoptosis. All the three Bim isoforms, BimEL, BimL and BimS, which exert comparable activity, 27,28 were upregulated by FK506 in two different samples ( Figure 5B). Similarly, the levels of expression of Bcl-2 modifying factor or Bmf were also increased ( Figure 5C).…”

p21-activated Kinase 2 (PAK2) Inhibits TGF-β Signaling in Madin-Darby Canine Kidney (MDCK) Epithelial Cells by Interfering with the Receptor-Smad Interaction

“…4E). Finally, we tested the expression of several TGF-␤ target genes, including Smad7, c-Myc, and Bim (32)(33)(34)(35)(36). As shown in Fig.…”

Upregulation of two BH3-only proteins, Bmf and Bim, during TGFβ-induced apoptosis

“…Other proteins that play a facilitative role in TGFb-induced death, but whose expression is not induced by it, include the adaptor proteins DAXX (Perlman et al, 2001) and CD2AP (Schiffer et al, 2004) and the septin ARTS- (Larisch et al, 2000). In addition, the proapoptotic Bcl-2 family protein Bim is a Smad3-dependent TGFb-induced protein in B lymphocytes (Wildey et al, 2003), whose binding to Bcl-X L increases during TGFb-induced apoptosis (Ohgushi et al, 2005). Furthermore, Bad and Bid (Kim et al, 2004) undergo caspase-dependent cleavage to more potently apoptotic forms after TGFb stimulation, while the antiapoptotic proteins Bcl-X L and Bcl-2 have been demonstrated to undergo TGFb-mediated downregulation in several cell types (Saltzman et al, 1998;Francis et al, 2000;Chipuk et al, 2001;Kanamaru et al, 2002).…”