IAP Suppression of Apoptosis Involves Distinct Mechanisms: the TAK1/JNK1 Signaling Cascade and Caspase Inhibition

Abstract

The antiapoptotic properties of the inhibitor of apoptosis (IAP) family of proteins have been linked to caspase inhibition. We have previously described an alternative mechanism of XIAP inhibition of apoptosis that depends on the selective activation of JNK1. Here we report that two other members of the IAP family, NAIP and ML-IAP, both activate JNK1. Expression of catalytically inactive JNK1 blocks NAIP and ML-IAP protection against ICE-and TNF-␣-induced apoptosis, indicating that JNK1 activation is necessary for the antiapoptotic effect of these proteins. The MAP3 kinase, TAK1, appears to be an essential component of this antiapoptotic pathway since IAP-mediated activation of JNK1, as well as protection against TNF-␣-and ICE-induced apoptosis, is inhibited when catalytically inactive TAK1 is expressed. In addition, XIAP, NAIP, and JNK1 bind to TAK1. Importantly, expression of catalytically inactive TAK1 did not affect XIAP inhibition of caspase activity. These data suggest that XIAP's antiapoptotic activity is achieved by two separate mechanisms: one requiring TAK1-dependent JNK1 activation and the second involving caspase inhibition.

Combined inhibition of PAK7, MAP3K7 and CK2α kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts

“…20 However, several members of the IAP (inhibitors of apoptosis) family, such as XIAP, NAIP and ML-IAP, activate JNK1 survival pathway through interaction with MAP3K7 and its activator TAB1. 21 Whether MAP3K7 can be pro-apoptotic or promote survival in the same cell, depending on conditions, or whether the two opposite functions are tissue specific is unknown.…”

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

“…(26) Moreover, JNK1 not JNK2, has been reported to be involved in BMP2-induced osteoblastic differentiation in MC3T3-L1 cells (27) ; also activated by TAK1, a BMP2-activated kinase, it thereby inhibits TNF-a-induced apoptosis in MCF7 cells. (28,29) These studies indicate that JNK1 is important in BMP2-induced osteoblastic differentiation. However, the exact role and the underlying mechanism mediated by JNK1 to regulate Runx2 expression or activity, which in turn affects osteoblastic differentiation, are unclear.…”

Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia

“…52 However, in many systems, TNF-␣-induced JNK activation does not induce apoptosis and has even been reported to be cytoprotective. 53 It also has been demonstrated that TNF-␣ can be a synergistic inducer of proliferation in immature CD34 ϩ /CD38 cells 34 and may induce proliferation of multipotent hematopoietic progenitors while inhibiting the development of committed progenitors. 54 HCD57 erythroleukemia cells are arrested at an early stage in erythroid development, as evidenced by the fact that forced expression of the activator protein-1 (AP1) transcription factor JunB induced the expression of some mature erythroid markers such as ␤-globin and spectrin-␣ and required at least 48 hours before these markers were seen.…”