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Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
Amplification in Myc oncogene has been detected during the initiation (PIN lesions) phase of prostate cancer and also during advanced stage [97, 99, 124, 125]. Myc can be amplified in prostate cancer by long-range regulatory regions in cancer cells or due to the inactivating mutation of the transcriptional repressor, FOXP3 [99]. Myc overexpression has been shown to immortalize prostate cells and together with Pim1, it can promote carcinoma with neuroendocrine differentiation [126, 127].
FLT3: A Receptor Tyrosine Kinase Target in Adult and Pediatric AML
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Mark Levis, Patrick Brown, Donald Small
The signaling properties of an FLT3 receptor with an ITD mutation differ from those of the wild-type receptor in a manner that clearly contributes to the process of leukemogenesis. STAT5 and FOXO transcription factors are abnormally activated in response to FLT3/ITD, but not FLT3 wild type, signaling (72–75). Microarray studies have identified upregulation of the Pim-1 and Pim-2 proto-oncogenes, as well as interaction with the Wnt signaling pathway, in FLT3/ITD leukemia cells (72,76,77). Finally, c/EBPα, a transcription factor involved in myeloid differentiation, is downregulated by the mutant receptors, indicative of the differentiation block that so characterizes leukemia cells (72,78). This downregulation is possibly mediated by RGS2 (74).
Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The murine and human pim-l gene code for a 313-amino acid Pim-1 protein of 34 kDa.613-615 In addition, the murine pim-l gene encodes an amino-terminal extension protein of 44 kDa, which is synthesized by alternative translation initiation of an upstream CUG codon.616 The human pim-l gene product was initially believed to be represented by a tyrosine kinase,617 but recent evidence unequivocally indicates that the kinase activity intrinsic to the murine and human Pim-1 protein is specific for serine/threonine residues.618-620 The pim-l gene is expressed in hematopoietic tissues as well as in testis and ovaries, but the precise role of the Pim-1 protein kinase is unknown.621 Consecutive inactivation of both pim-l proto-oncogene alleles by homologous recombination in mouse embryonic stem cells shows that the Pim-1 protein is not required for the normal growth and differentiation of these cells.
Targeting PRAS40: a novel therapeutic strategy for human diseases
Published in Journal of Drug Targeting, 2021
Qun Zhou, Shengsong Tang, Xianhui Zhang, Linxi Chen
PIM1 is a serine/threonine kinase with a variety of biological effects such as cell survival, proliferation and differentiation [68]. PRAS40 is a known substrate of Akt and PIM, and it has been proved that PRAS40 is phosphorylated independently at Thr246 site. Zhang et al found that the overexpression of PIM1 increased the level of phosphorylation at PRAS40-Thr246, indicating that PIM1 regulates the activity of mTOR through the phosphorylation of PRAS40. The detection of kinase in vitro further showed that PIM1 could directly phosphorylate the PRAS40-Thr246 site. Overexpression of PIM1 reduces the association between PRAS40 and mTOR [68]. Subbannayya et al. [23] reported that the regulation of PRAS40 activity by inhibiting its upstream kinase PIM1 can significantly reduce the proliferation, colony formation and invasion ability of GBC cells, and the inhibition of PIM1 is through the inhibition of PRAS40 phosphorylation to regulate mTOR signal transduction. Velazquez et al. [69] also confirmed that the phosphorylation of PRAS40 was regulated by PIM1 that a protein kinase of the native gene family, and the level of phosphorylated PRAS40 can be reduced by inhibiting PIM1. In conclusion, PIM1 participates in the regulation of PRAS40 phosphorylation and is related to Thr246 site.
Synthesis of new pyridothienopyrimidinone and pyridothienotriazolopyrimidine derivatives as pim-1 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Hala B. El-Nassan, Bassem H. Naguib, Engy A. Beshay
The proviral integration site for Moloney murine leukaemia virus-1 (known as pim-1) is a serine/threonine kinase that controls many cellular functions including cell cycle, cell differentiation, cell survival, apoptosis and drug resistance1–3. High levels of pim-1 kinase are associated with many types of cancer such as myeloid leukaemia, breast cancer and prostatic cancer1–4. The identification of the role of pim-1 in controlling the growth of cancer stem cells and promotion of multiple drug resistance added more to the importance of developing potent pim-1 inhibitors as anticancer agents that can overcome the drug resistance developed by cancer stem cells1,5.
Integrated molecular docking, 3D QSAR and molecular dynamics simulation studies on indole derivatives for designing new Pim-1 inhibitors
Published in Journal of Receptors and Signal Transduction, 2020
Sudhir Reddy Peddi, Saikiran Reddy Peddi, Sreekanth Sivan, Radhika Veerati, Vijjulatha Manga
The Proviral integration site for Moloney murine leukemia virus-1 (pim-1) which encodes for serine/threonine kinase has an oncogenic potential [1]. It is known to involve in multiple cellular functions such as cell growth, differentiation, survival, tumorigenesis and apoptosis [2,3]. Pim-1 was originally described in relation to murine T-cell lymphomas but subsequently implicated in numerous human cancers, including acute myeloid leukemia, prostate cancer and other hematopoietic malignancies [4]. Pim-1 is also associated with cytokine signaling and instigates many signal transduction pathways. It acts as downstream target for JAK/STAT signaling pathway.