Involvement of endoplasmic reticulum stress in tauopathy.

Tauopathy is a pathological condition with an abnormal intracellular accumulation of tau protein in neurons and glias, which is a feature of Alzheimer's disease (AD) as well as frontotemporal lobar degenerations (FTLD). Recent reports showed that tauopathy occupies an important position for pathological process of dementia generally. Previously, we reported that endoplasmic reticulum (ER) stress has an influence on the onset of AD. In addition, some reports on brain autopsy findings suggest that ER stress is associated with AD and tauopathy. However, the mechanism underlying the association between ER stress and tauopathy is still unknown. Here, we show that ER stress, induced by glucose deprivation or chemicals, increases total endogenous tau protein in cultured neurons and primary cultured neurons. Under ER stress, no significant differences were observed in the transcription of tau, and no differences were observed in the translation of tau with or without the 5'-untranslated region (5'UTR) of tau. In contrast, the degradation rate of tau was decreased by 20% under ER stress. ER stress reduced the binding between tau and carboxyl terminus of Hsc70-interacting protein (CHIP), ubiquitin E3 ligase for tau. These results suggest that ER stress increases total tau protein and its mechanism is due to the decrease in the binding between tau and CHIP, which delays the degradation of tau protein through the ubiquitin-proteasome pathway. This mechanism may provide clue to treatment for tauopathy.

AIB1 promotes DNA replication by JNK repression and AKT activation during cellular stress.

Amplified in breast cancer 1 (AIB1) is a member of the p160 family of nuclear receptor coactivator protein. Recent studies have reported that high-level AIB1 production is involved in the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway for progression to malignant carcinoma in a steroid-independent manner. Here we demonstrate that, in AIB1-knockout DT40 chicken B-lymphocytes, loss of AIB1 results in induction of phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, in addition to the inhibition of DNA replication. In contrast, high-level AIB1 production prevents proapoptotic activation of the JNK/c-Jun signal transduction pathway and induces DNA replication through phosphorylation of the Akt/p65 NF-kappaB subunit RelA under cellular stresses such as UV irradiation or serum deprivation. Moreover, we have found that AIB1 is essential for the phosphorylation of histone H3 at serine 10, which is associated with the signal transduction to chromatin, leading to the transient expression of immediate-early genes in response to UV stimulation. Our results therefore suggest that AIB1 directly links to cell cycle control mechanisms in concern with the balance between apoptosis and proliferation.