JOURNAL ARTICLE

Inhibition of the c-Jun N-terminal kinase signaling pathway by the mixed lineage kinase inhibitor CEP-1347 (KT7515) preserves metabolism and growth of trophic factor-deprived neurons

Charles A Harris, Mohanish Deshmukh, Brian Tsui-Pierchala, Anna C Maroney, Eugene M Johnson
Journal of Neuroscience 2002 January 1, 22 (1): 103-13
11756493
Nerve growth factor (NGF) deprivation triggers metabolic changes in sympathetic neurons that precede cell death. Here, we investigate the role of the c-Jun N-terminal kinase (JNK) pathway in downregulating neuronal metabolism. We show that, in the presence of CEP-1347 (KT7515), a small molecule known to block cell death upstream of JNK, cellular metabolism is preserved in neurons deprived of NGF. Biochemical data that are presented are consistent with the mechanism of action of CEP-1347 being the inhibition of the mixed lineage kinases (MLKs), known activators of JNK signaling. We demonstrate that CEP-1347-saved neurons continue to grow even in the absence of NGF, indicating that inhibition of the JNK pathway is permissive for neuronal growth in the absence of trophic support. These trophic effects are seen despite the fact that CEP-1347 does not stimulate several known survival kinase pathways. In addition to blocking Bax-dependent cytochrome c release, the inhibition of the JNK signaling pathway with CEP-1347 also blocks the development of competence-to-die in response to cytosolic cytochrome c. Therefore, inhibition of the JNK signaling pathway with the MLK inhibitor CEP-1347 inhibits both limbs of the apoptotic pathway. Finally, we demonstrate that neurons that have been NGF-deprived long-term but that have been kept alive by caspase inhibitors can be rescued metabolically by CEP-1347 as assessed by soma size, cytochrome c localization, and protein synthesis rates. Therefore, we conclude that, in addition to converting extracellular signals into decisions of life and death, the JNK pathway can modulate cellular metabolism directly and thereby maintain not only survival but the "quality of life" of neurons.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Remove bar
Read by QxMD icon Read
11756493
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"