Mutually exclusive subsets of BH3-only proteins are activated by the p53 and c-Jun N-terminal kinase/c-Jun signaling pathways during cortical neuron apoptosis induced by arsenite.

نویسندگان

  • Hon Kit Wong
  • Michael Fricker
  • Andreas Wyttenbach
  • Andreas Villunger
  • Ewa M Michalak
  • Andreas Strasser
  • Aviva M Tolkovsky
چکیده

The c-Jun N-terminal protein kinase (JNK)/c-Jun and p53 pathways form distinct death-signaling modules in neurons that culminate in Bax-dependent apoptosis. To investigate whether this signaling autonomy is due to recruitment of particular BH3-only proteins, we searched for a toxic signal that would activate both pathways in the same set of neurons. We show that arsenite activates both the JNK/c-Jun and p53 pathways in cortical neurons, which together account for >95% of apoptosis, as determined by using the mixed-lineage kinase (JNK/c-Jun) pathway inhibitor CEP11004 and p53-null mice. Despite the coexistence of both pathways in at least 30% of the population, Bim mRNA and protein expression was increased only by the JNK/c-Jun signaling pathway, whereas Noxa and Puma mRNA and Puma protein expression was entirely JNK/c-Jun independent. About 50% of Puma/Noxa expression was p53 dependent, with the remaining signal being independent of both pathways and possibly facilitated by arsenite-induced reduction in P-Akt. However, functionally, Puma was predominant in mediating Bax-dependent apoptosis, as evidenced by the fact that more than 90% of apoptosis was prevented in Puma-null neurons, although Bim was still upregulated, while Bim- and Noxa-null neurons died similarly to wild-type neurons. Thus, the p53 and JNK/c-Jun pathways can activate mutually exclusive subclasses of BH3-only proteins in the same set of neurons. However, other factors besides expression may determine which BH3-only proteins mediate apoptosis.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Arsenite-induced apoptosis in cortical neurons is mediated by c-Jun N-terminal protein kinase 3 and p38 mitogen-activated protein kinase.

c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase are activated by stress and are implicated in regulation of apoptosis in several tissues. However, their contribution to stress-induced apoptosis in CNS neurons is not well defined. Here we investigated the role of JNK and p38 in cortical neuron apoptosis caused by sodium arsenite treatment. Sodium arsenite is an env...

متن کامل

Modulation of H2O2- Induced Neurite Outgrowth Impairment and Apoptosis in PC12 Cells by a 1,2,4-Triazine Derivative

Introduction: Increased oxidative stress is widely accepted to be a factor in the development and progression of Alzheimer’s disease. Triazine derivatives possess a wide range of pharmacological activities including anti-oxidative and anti-in.ammatory actions. In this study, we aimed to investigate the possible protective effect of 3-thioethyl-5,6-dimethoxyphenyl-1,2,4-triazine (TEDMT) on H2O2-...

متن کامل

The Implication of Androgens in the Presence of Protein Kinase C to Repair Alzheimer’s Disease-Induced Cognitive Dysfunction

Aging, as a major risk factor of memory deficiency, affects neural signaling pathways in hippocampus. In particular, age-dependent androgens deficiency causes cognitive impairments. Several enzymes like protein kinase C (PKC) are involved in memory deficiency. Indeed, PKC regulatory process mediates α-secretase activation to cleave APP in β-amyloid cascade and tau proteins phosphorylation mecha...

متن کامل

Inactivation of mitogen-activated protein kinase signaling pathway reduces caspase-14 expression in impaired keratinocytes

Objective(s):Several investigations have revealed that caspase-14 is responsible for the epidermal differentiation and cornification, as well as the regulation of moisturizing effect. However, the precise regulation mechanism is still not clear. This study was aimed to investigate the expression of caspase-14 in filaggrin-deficient normal human epidermal keratinocytes (NHEKs) and to explore the...

متن کامل

Brain Targeting of 1,9-Pyrazoloanthrone an c-Jun-N-terminal Kinase Inhibitor Using Liposomes for Effective Management of Parkinson’s Disease

The major challenge to treat Parkinson’s disease (PD) is penetration of target molecule into the brain to improve the efficacy of drugs. To achieve better brain penetration and targeted delivery, 1,9-Pyrazoloanthrone (1,9-P) loaded liposomes were developed by solvent injection technique using ultrasonication and evaluated for particle size, morphology, entrapment efficiency, FT-IR, and in-vitro...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Molecular and cellular biology

دوره 25 19  شماره 

صفحات  -

تاریخ انتشار 2005