[Show abstract][Hide abstract] ABSTRACT: The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO-induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons.
Genes & development 02/2011; 25(4):310-22. DOI:10.1101/gad.1984311 · 10.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The cJun NH2-terminal kinase (JNK) signal transduction pathway has been implicated in mammary carcinogenesis. To test the role of JNK, we examined the effect of ablation of the Jnk1 and Jnk2 genes in a Trp53-dependent model of breast cancer using BALB/c mice. We detected no defects in mammary gland development in virgin mice or during lactation and involution in control studies of Jnk1(-/-) and Jnk2(-/-) mice. In a Trp53(-/+) genetic background, mammary carcinomas were detected in 43% of control mice, 70% of Jnk1(-/-) mice, and 53% of Jnk2(-/-) mice. These data indicate that JNK1 and JNK2 are not essential for mammary carcinoma development in the Trp53(-/+) BALB/c model of breast cancer. In contrast, this analysis suggests that JNK may partially contribute to tumor suppression. This conclusion is consistent with the finding that tumor-free survival of JNK-deficient Trp53(-/+) mice was significantly reduced compared with control Trp53(-/+) mice. We conclude that JNK1 and JNK2 can act as suppressors of mammary tumor development.
PLoS ONE 08/2010; 5(8):e12469. DOI:10.1371/journal.pone.0012469 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic-pituitary-thyroid axis. Disruption of thyroid hormone function prevents the effects of nervous system JNK1 deficiency on body mass. These data demonstrate that the hypothalamic-pituitary-thyroid axis represents an important target of metabolic signaling by JNK1.
Genes & development 02/2010; 24(3):256-64. DOI:10.1101/gad.1878510 · 10.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The c-Jun NH(2)-terminal kinase isoform (JNK) 1 is implicated in type 2 diabetes. However, a potential role for the JNK2 protein kinase in diabetes has not been established. Here, we demonstrate that JNK2 may play an important role in type 1 (insulin-dependent) diabetes that is caused by autoimmune destruction of beta cells. Studies of nonobese diabetic mice demonstrated that disruption of the Mapk9 gene (which encodes the JNK2 protein kinase) decreased destructive insulitis and reduced disease progression to diabetes. CD4(+) T cells from JNK2-deficient nonobese diabetic mice produced less IFN-gamma but significantly increased amounts of IL-4 and IL-5, indicating polarization toward the Th2 phenotype. This role of JNK2 to control the Th1/Th2 balance of the immune response represents a mechanism of protection against autoimmune diabetes. We conclude that JNK protein kinases may have important roles in diabetes, including functions of JNK1 in type 2 diabetes and JNK2 in type 1 diabetes.
Proceedings of the National Academy of Sciences 06/2005; 102(19):6931-5. DOI:10.1073/pnas.0502143102 · 9.67 Impact Factor