title: PTBP1 modulation of MCL1 expression regulates cellular apoptosis induced by antitubulin chemotherapeutics.
abstract: Myeloid cell leukemia sequence 1 (MCL1), an anti-apoptotic BCL2 family protein, is a key regulator of intrinsic apoptosis. Normal cells require strict control over MCL1 expression with aberrant MCL1 expression linked to the emergence of various diseases and chemoresistance. Previous studies have detailed how MCL1 expression is regulated by multiple mechanisms both transcriptionally and translationally. However, characterization of the post-transcriptional regulators of MCL1 mRNA is limited. Polypyrimidine tract binding protein 1 (PTBP1) is a known regulator of post-transcriptional gene expression that can control mRNA splicing, translation, stability and localization. Here we demonstrate that PTBP1 binds to MCL1 mRNA and that knockdown of PTBP1 upregulates MCL1 expression in cancer cells by stabilizing MCL1 mRNA and increasing MCL1 mRNA accumulation in cytoplasm. Further, we show that depletion of PTBP1 protects cancer cells from antitubulin agent-induced apoptosis in a MCL1-dependent manner. Taken together, our findings suggest that PTBP1 is a novel regulator of MCL1 mRNA by which it controls apoptotic response to antitubulin chemotherapeutics.
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Placzek
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism*; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C450006:PTBP1 protein, human; D012333:RNA, Messenger; D050257:Tubulin Modulators; D038941:Polypyrimidine Tract-Binding Protein