The residues of the bottom group (Gln127, Asp128, and Leu174 in Pim1) were crucial for Pims/PIM447 systems, while the contributions of these residues were decreased sharply for Pims/AZD1208 systems.
For different GB cell lines, Western Blot, mitochondrial fractionation, fluorescence microscopy, effector caspase assays, flow cytometry, and an adult organotypic brain slice transplantation model were used to investigate the putative PIM1/MCL1 signaling axis regarding potential synergistic effects with ABT-737.
Sotrastaurin decreased the expression of pro-survival protein myeloid cell leukemia (MCL-1) and the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), both of which are downstream effectors of PIM-1.
Overall, our results demonstrate that STAT5, in part by upregulating PIM1 activity, plays a major role in mediating the leukemia-promoting effects of IL-7/IL-7R.
The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors.
Together, these studies indicate that targeting STAT5 or STAT5-regulated pathways may provide a new approach for therapy development in Ph+ ALL, especially the relapsed/TKI-resistant disease.<b>Significance:</b> Suppression of STAT5 by BCL2 and PIM kinase inhibitors reduces leukemia burden in mice and constitutes a new potential therapeutic approach against Ph+ ALL, especially in tyrosine kinase inhibitor-resistant disease.<i></i>.
Proviral Integration site for Moloney murine leukemia virus-1 (PIM1) belongs to the serine/threonine kinase family of Ca<sup>2+</sup>-calmodulin-dependent protein kinase (CAMK) group, which is involved in cell survival and proliferation as well as a number of other signal transduction pathways.
Provirus integration site for Moloney murine leukemia virus 1 (Pim-1) has proved to be an oncogene and it is known that to depress Pim-1 activity may be a novel oncological treatment strategy.
This study suggests that PIM1 could be a valuable prognostic marker in patients with OS, and the biological functions of PIM kinase family in the osteosarcoma cell lines indicate that they could serve as potential therapeutic targets for OS.
Similar to the other Pim kinases (Pim-1 and Pim-2), Pim-3 is involved in many cellular processes, including cell proliferation, survival, and protein synthesis.
Studies in transgenic mice showed the key role of (Pim-1) (proviral integration site for Moloney murine leukemia virus-1) in the control of cardiomyocyte function and viability.
Targeting Pim-1 with monoclonal antibody could be explored for the treatment of leukemia and may represent a novel strategy to overcome drug resistance.
The bcr-abl/M-induced tumors also showed recurring proviral integration near c-myc, Pim-1 and Mlvi-1, albeit at a lower frequency than seen in the Mo-MuLV tumors.