Repression of phospho‐JNK and infarct volume in ischemic brain of JIP1‐deficient mice

Abstract

Mice lacking JIP1, a scaffold protein that organizes JNK pathway components, were constructed independently by two groups. The proposed in vivo function, however, remains contradictory; One study reported that targeted disruption of the jip1 caused embryonic death due to the requirement of JIP1 for fertilized eggs (Thompson et al. [2001] J. Biol. Chem. 276:27745-27748). In contrast, another group (Whitmarsh et al. [2001] Genes Dev. 15:2421-2432) demonstrated that JIP1-deficient mice were viable and that the JIP1 null mutation inhibited the kainic acid-induced JNK activation and neuronal death. The current study was undertaken to re-elucidate the in vivo roles of JIP1 using newly generated JIP1 knockout mice. Our JIP1-deficient mice were viable and healthy. The transient focal ischemic insult produced by middle cerebral artery occlusion (MCAO) strongly activated JNK in brain of jip1(+/+), jip1(+/-), and jip1(-/-) mice. Increased JNK activity was sustained for more than 22 hr in jip1(+/+) and jip1(+/-), whereas it was repressed rapidly in jip1(-/-). Concomitantly, the infarct volume produced by the ischemic insult in jip1(-/-) was reduced notably compared to that in jip1(+/+) brain. These results suggest that JIP1 plays a pivotal role in regulating the maintenance of phosphorylated JNK and neuronal survival in postischemic brain, but is not essential for JNK activation and early development.

Requirement of JIP scaffold proteins for NMDA-mediated signal transduction

“…2C). As expected Im et al 2003), JIP deficiency caused defects in JNK activity in primary neurons in vitro (Fig. 2D,E) and the brain in vivo (Fig.…”

“…Indeed, studies of JIP1-deficient mice confirm that this scaffold protein is essential for some forms of stress-induced JNK activation (Morrison and Davis 2003). Thus, JIP1 is required for JNK activation and neuronal death in response to ischemia in vitro and stroke in vivo Im et al 2003) and for JNK-mediated insulin resistance in type II diabetes (Jaeschke et al 2004).…”

“…Together, these observations suggest that JIP1-deficient mice should have major physiological defects. However, JIP1-deficient mice exhibit only a limited spectrum of defects, including the response to ischemia Im et al 2003) and metabolic stress (Jaeschke et al 2004).…”

Role of the JIP4 Scaffold Protein in the Regulation of Mitogen-Activated Protein Kinase Signaling Pathways

“…Gene disruption studies with mice (9,29,34) have demonstrated that JIP1 contributes to JNK activation in neurons following exposure to an anoxic insult (9,34) and is also required in adipose tissue for JNK activation in models of type II diabetes (11). Together, these data provide strong genetic evidence that the JIP proteins can function to regulate JNK signaling.…”

JIP1 binding to RBP-Jk mediates cross-talk between the Notch1 and JIP1-JNK signaling pathway

“…The cultured cells were transiently transfected by the calcium phosphate method or Lipofectamine (Invitrogen, Camarillo, CA, USA). 17,18,27 Cloning and preparation of recombinant proteins. Mouse Notch1-IC and RBP-Jk cDNAs and deletion mutants were constructed through standard PCR, and inserted into the bacterial expression vector, pGEX4T-3 (Amersham Pharmacia, Piscataway, NJ, USA) as described earlier.…”