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GSK3βmediated Ser156 phosphorylation modulates a BH3like domain in BCL2L12 during TMZinduced apoptosis and autophagy in glioma cells

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BH3 domains, classified initially as BCL2 homology domains, participate in both apoptosis and autophagy. Beclin1 contains a BH3 domain, which is required for binding to antiapoptotic BCL2 homologs and BCL2mediated inhibition of autophagy. BCL2like 12 (BCL2L12) also harbors a BH3like domain, which is 12 residues long and contains a LXXXAE/D motif. In a yeast twohybrid system performed in the present study, BCL2L12 shared similar binding partnerships to antiapoptotic BCL2 homologs, such as Beclin1. In addition, this BH3like domain was involved in antiapoptosis and druginduced autophagy in glioma cell lines. Mutations in S156 and hydrophobic L213 to alanine counteracted the antiapoptotic properties of BCL2L12 and downregulated the activation of microtubule associated protein 1 light chain 3B (LC3B), autophagyrelated (ATG)12ATG5 conjugates and Beclin1, compared with a BCL2L12 wildtype group. Molecular dynamics simulations revealed that phosphorylation at Ser156 of BCL2L12 (within α6 and α7 helices) influenced the BH3like domain conformation (α9 helix), indicating that glycogen synthase kinase (GSK) 3βmediated Ser156 phosphorylation modulated a BH3like domain in BCL2L12. Altogether, the present findings indicated that BCL2L12 may participate in antiapoptosis and autophagy via a BH3like domain and GSK3βmediated phosphorylation at Ser156. Furthermore, blockade of temozolomide (TMZ)induced autophagy by 3methyladenine (3MA) resulted in enhanced activation of apoptotic markers, as well as tumor suppresor protein p53 (p53) expression in U87MG cells. The present results suggested that p53 and O6methylguanine DNA methyltransferase activation, and BCL2, BCLextra large, Beclin1 and BCL2L12 expression may be used as a detection panel to determine which patients can benefit from TMZ and ABT737 combination treatment.
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Document Type: Research Article

Affiliations: 1: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C. 2: Laboratories of Medical Research, Center for Education and Faculty Development, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan, R.O.C. 3: Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C.

Publication date: January 1, 2018

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  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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