Transforming Growth Factor-β1 (TGF-β)–induced Apoptosis of Prostate Cancer Cells Involves Smad7-dependent Activation of p38 by TGF-β-activated Kinase 1 and Mitogen-activated Protein Kinase Kinase 3

Abstract

The inhibitory Smad7, a direct target gene for transforming growth factor-β (TGF-β), mediates TGF-β1–induced apoptosis in several cell types. Herein, we report that apoptosis of human prostate cancer PC-3U cells induced by TGF-β1 or Smad7 overexpression is caused by a specific activation of the p38 mitogen-activated protein kinase pathway in a TGF-β–activated kinase 1 (TAK1)- and mitogen-activated protein kinase kinase 3 (MKK3)-dependent manner. Expression of dominant negative p38, dominant negative MKK3, or incubation with the p38 selective inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], prevented TGF-β1–induced apoptosis. The expression of Smad7 was required for TGF-β–induced activation of MKK3 and p38 kinases, and endogenous Smad7 was found to interact with phosphorylated p38 in a ligand-dependent manner. Ectopic expression of wild-type TAK1 promoted TGF-β1–induced phosphorylation of p38 and apoptosis, whereas dominant negative TAK1 reduced TGF-β1–induced phosphorylation of p38 and apoptosis. Endogenous Smad7 was found to interact with TAK1, and TAK1, MKK3, and p38 were coimmunoprecipitated with Smad7 in transiently transfected COS1 cells. Moreover, ectopically expressed Smad7 enhanced the coimmunoprecipitation of HA-MKK3 and Flag-p38, supporting the notion that Smad7 may act as a scaffolding protein and facilitate TAK1- and MKK3-mediated activation of p38.

The role of bone morphogenetic proteins in myeloma cell survival

“…[19] This pathway also depends on SMAD7 as a scaffolding protein, enabling activation of p38. [20] R-SMAD-dependent pathways are also involved in apoptosis and one important regulator of apoptosis, the tumor suppressor gene Other mechanisms by which I-SMADs regulate SMAD signaling include prevention of R-SMAD/SMAD4 heteromerization by binding to SMAD4, recruitment of SMURFs to receptors leading to receptor degradation, and direct inhibition of transcriptional responses. [27] SMAD7 inhibits both TGF-β and BMP signaling, whereas SMAD6 mainly inhibits BMP signaling, and more efficiently signaling by ALK3/6 than ALK1/2.…”

Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions

“…MAP3K7 exerts these effects by interacting with a number of different signaling pathways and activator molecules. [7][8][9][10] For example, MAP3K7 can be activated by TGF-b and BMP. 8,11,12 MAP3K7 is one of the first kinases in the p38 and JNK signaling pathways.…”

“…[7][8][9][10] For example, MAP3K7 can be activated by TGF-b and BMP. 8,11,12 MAP3K7 is one of the first kinases in the p38 and JNK signaling pathways. 8,13,14 MAP3K7 also has an important role in the balance between the BMP-and WNT-signaling pathways.…”

“…8,11,12 MAP3K7 is one of the first kinases in the p38 and JNK signaling pathways. 8,13,14 MAP3K7 also has an important role in the balance between the BMP-and WNT-signaling pathways. 7,15 The clinical effects of MAP3K7 alterations are unclear.…”

TGF-β-activated Kinase-1: A Potential Prognostic Marker for Clear Cell Renal Cell Carcinoma

“…Therefore, novel diagnostic and prognostic markers of ccRCC would be very valuable in high-risk people and in those with existing TGF-β-activated kinase-1 (TAK1) is a member of mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK), and is an indispensable signaling intermediate in several MAPK and NF-κB pathways (Ninomiya et al, 1999;Takaesu et al, 2001;Shim et al, 2005). TAK1 activity has been related to a greater aggressiveness in several types of cancer (Kondo et al, 1998;Edlund et al, 2003;Kaur et al, 2005), but the underlying mechanisms is not clear until now. Moreover, the relationship between TAK1 expression and prognosis status is still ambiguous.…”