Induction of neuronal apoptosis by expression of Hes6 via p53-dependent pathway

• Published in: Brain research 2010-02, Vol.1313, p.1-8
• Main Authors: Eun, Bokkee, Cho, Bongki, Moon, Younghye, Kim, Soo Young, Kim, Kyungjin, Kim, Hyun, Sun, Woong
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Animals; Apoptosis - physiology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Brain - embryology; Brain - growth & development; Brain - physiology; Cell physiology; Cells, Cultured; Cerebral Cortex - embryology; Cerebral Cortex - growth & development; Cerebral Cortex - physiology; Cytoplasm - metabolism; Fundamental and applied biological sciences. Psychology; HeLa Cells; Hes6; Humans; Mice; Mice, Knockout; Mitochondria; Molecular and cellular biology; Neurology; Neuronal cell death; Neurons - physiology; Nuclear; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Sprague-Dawley; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA, Messenger - metabolism; Signal Transduction; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.11.078

Abstract Hes6 is a member of hairy/enhancer of split (Hes) family that plays a role in the cell proliferation and differentiation. Recently, we found that Hes6 is involved in the regulation of cell proliferation via p53-dependent pathway. In addition to the proliferating regions, brain regions where early post-mitotic neurons are enriched also exhibited Hes6 and p53 mRNA expression. Because p53 is involved in the post-mitotic neuronal apoptosis, here we investigated whether Hes6 can influence the neuronal survival/death. Overexpression of wild-type Hes6 and its mutants induced the apoptosis of primary cultured cortical neurons. In addition, neuronal apoptosis by Hes6 overexpression was markedly blunted in p53−/− or Bax−/− cortical neurons, suggesting that these pro-apoptotic effects are mediated by p53- and Bax-dependent pathway. However, transactivation-defective mutants of Hes6 also enhanced neuronal apoptosis, suggesting that apoptogenic activity of Hes6 is not directly related to its role in the transcriptional regulation. We propose that Hes6 may play a significant role in the neuronal cell death and/or pathological neurodegeneration via activation of p53 signaling.