ABSTRACT
<p><b>OBJECTIVE</b>To explore the role of PDK1 in T-ALL development through establishing the Notch1-induced T-ALL mouse model by using Mx1-cre; LoxP system to knock-out PDK1.</p><p><b>METHODS</b>Cell cycle and apoptosis of leukemic cells were detected by flow cytometry, and relative expression of tumor-related genes and transcription factors of leukemic cells were determined by quantitative real-time PCR.</p><p><b>RESULTS</b>Notch1-induced T-ALL mouse model with inducible knock-out of PDK1 was established successfully. Compared to T-ALL control mouse model, PDK1 knock-out mice showed a significant longer survival time (P<0.01). There was no difference of cell cycle between control and PDK1 knock-out mice, and the apoptosis rate of leukemic cells in PDK1 knock-out mice was higher than that of control mice (P<0.001). PDK1 knock-out resulted in decreased expression of tumor-related genes and transcription factors, such as c-Myc and NF-κB (P<0.01), and increased expression level of P53 (P<0.01).</p><p><b>CONCLUSION</b>PDK1 knock-out can inhibit the development of T-ALL, and its mechanism may be the leukemia progression inhibited by regulating the apoptosis and expression of multiple related genes and transcription factors.</p>
Subject(s)
Animals , Mice , Apoptosis , Cell Cycle , Disease Models, Animal , Gene Expression Regulation, Leukemic , Mice, Knockout , NF-kappa B , Genetics , Metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Genetics , Protein Serine-Threonine Kinases , Genetics , Proto-Oncogene Proteins c-myc , Genetics , Metabolism , Real-Time Polymerase Chain Reaction , Receptor, Notch1 , Genetics , Tumor Suppressor Protein p53 , Genetics , MetabolismABSTRACT
Mammalian target of rapamycin complex (mTORC) is an important center for regulating cellular growth, survival and metabolism. mTORC plays a vital role in maintenance of normal physiological activities and homeostasis in organism. According to protein components, mTORC can be divided into two distinct protein complexes: mTORC1 and mTORC2. The main protein components of mTORC2 include mTOR, Rictor, mLST8, Deptor, mSin1, Protor and Hsp70. By means of activating AKT, PKCα, SGK1 and so on, the mTORC regulates many vital activities:embryonic development, cytoskeletal reconstitution,cell migration and protein post-translational modification. The abnormality of mTORC2 signaling pathway has been confirmed to be associated with tumorigenesis, therefore, further understanding the components, functions and signalling pathway of mTORC2 will provide a new insights in developing targeted cancer therapy. In this review, the structure and signalling pathway of mTORC2 and its roles in hematological malignancies are discussed and summarised.