[No authors listed]
BH3 domains, classified initially as BCL2 homology domains, participate in both apoptosis and autophagy. Beclinâ1 contains a BH3 domain, which is required for binding to antiapoptotic BCL2 homologs and BCL2âmediated inhibition of autophagy. BCL2âlike 12 (BCL2L12) also harbors a BH3âlike domain, which is 12 residues long and contains a LXXXAE/D motif. In a yeast twoâhybrid system performed in the present study, BCL2L12 shared similar binding partnerships to antiapoptotic BCL2 homologs, such as Beclinâ1. In addition, this BH3âlike domain was involved in antiâapoptosis and drugâinduced 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), autophagyârelated (ATG)12âATG5 conjugates and Beclinâ1, compared with a BCL2L12 wildâtype group. Molecular dynamics simulations revealed that phosphorylation at Ser156 of BCL2L12 (within αâ6 and αâ7 helices) influenced the BH3âlike domain conformation (αâ9 helix), indicating that glycogen synthase kinase (GSK) 3βâmediated Ser156 phosphorylation modulated a BH3âlike domain in BCL2L12. Altogether, the present findings indicated that BCL2L12 may participate in antiâapoptosis and autophagy via a BH3âlike domain and GSK3βâmediated phosphorylation at Ser156. Furthermore, blockade of temozolomide (TMZ)âinduced autophagy by 3âmethyladenine (3âMA) 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 O6âmethylguanine DNA methyltransferase activation, and BCL2, BCLâextra large, Beclinâ1 and BCL2L12 expression may be used as a detection panel to determine which patients can benefit from TMZ and ABTâ737 combination treatment.
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