A systematic review on active sites and functions of PIM-1 protein

Zhao, Yumin; Aziz, Aziz Ur Rehman; Zhang, Hangyu; Zhang, Zhengyao; Li, Na; Liu, Bo

doi:10.1007/s13577-021-00656-3

Cited by 13 publications

(6 citation statements)

References 111 publications

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“…It should be noted that PIM1 , containing four AUUUA repeats, showed the strongest inhibitory activity and greatest response to TTP overexpression (Figure d,e). PIM1 is a type of protein kinase and contributes to solid cancers and hematologic malignancies, cell growth, proliferation, and other life activities. , We therefore determined to focus on PIM1 in this work. Either knockout of TTP or deletion of the PIM1 ARE expectedly resulted in a significant increase in EGFP expression (Figure f,g); also, the PIM1 3′ UTR without the ARE did not respond to overexpressing TTP (Figure S1), further confirming the regulatory activity of the PIM1 3′ UTR segment dependent on the TTP–ARE interaction.…”

Section: Resultsmentioning

confidence: 99%

Precise Interference of RNA–Protein Interaction by CRISPR-Cas13-Mediated Peptide Competition

Li,

Lin

et al. 2023

ACS Synth. Biol.

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RNA–protein interactions are essential nodes of cellular regulatory circuits and play critical roles in normal physiology and disease. However, the precise roles of individual RNA–protein interactions remain elusive. Here we report a method for precise interference of endogenous RNA interacting with the RNA binding protein (RBP). TTP is an RBP that recognizes the AU-rich element (ARE) of mRNA via the binding domain TZF and represses gene expression. We engineer Cas13b, a class 2 type VI CRISPR-Cas endonuclease that exclusively targets RNA, to direct the peptide of TZF to the binding site and compete with endogenous TTP. We show that this tool specifically interferes with TTP interacting with the PIM1 and IL-2 3′ UTR under the guidance of the gRNA specific for the AREs. Further, precise interference with the TTP–PIM1 interaction exerts a distinct effect on cell proliferation compared to transcriptome-wide interference. Thus, our work establishes a tool for deep understanding of RNA–RBP interactions.

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Section: Resultsmentioning

confidence: 99%

Precise Interference of RNA–Protein Interaction by CRISPR-Cas13-Mediated Peptide Competition

Li,

Lin

et al. 2023

ACS Synth. Biol.

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“…27,28 By designing inhibitors that target the unique ATP-binding site of PIM-1, selectivity can be achieved while avoiding interactions with other kinases that have different hinge region structures, a possibility suggested by the unique and characteristic structure of the PIM-1 kinase. 29 PIM-2 also has a similar structure to PIM-1 in the hinge region with a closed conformation and displays a bilobal kinase architecture similar to that of PIM-1. The backbone of the two kinases is similar except for two flexible regions in the N-terminal lobe, such as the absence of the αJ-helix in PIM-2, and the fact that PIM-2 contains six proline residues in the Nterminal kinase lobe (the last 23 residues) contain six proline residues, which increases flexibility and contributes to the disordered region of the PIM-2 kinase architecture (Figure 1C).…”

Section: Structures and Biological Functions Of Pimmentioning

confidence: 97%

“…The ATP-binding site in PIM-1 is surrounded by a hinge region (residue position: 121–126) that contains a proline residue at position Pro123. This proline residue forms a unique ATP-binding site in the hinge region that binds the natural substrate ATP through only one hydrogen bond (Figure B). , By designing inhibitors that target the unique ATP-binding site of PIM-1, selectivity can be achieved while avoiding interactions with other kinases that have different hinge region structures, a possibility suggested by the unique and characteristic structure of the PIM-1 kinase . PIM-2 also has a similar structure to PIM-1 in the hinge region with a closed conformation and displays a bilobal kinase architecture similar to that of PIM-1.…”

Section: Structures and Biological Functions Of Pimmentioning

confidence: 99%

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

Chen,

Mao,

Ren

et al. 2024

J. Med. Chem.

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Proviral integration sitea for Moloney-murine leukemia virus (PIM) kinases are a family of highly conserved serine/tyrosine kinases consisting of three members, PIM-1, PIM-2, and PIM-3. These kinases regulate a wide range of substrates through phosphorylation and affect key cellular processes such as transcription, translation, proliferation, apoptosis, and energy metabolism. Several PIM inhibitors are currently undergoing clinical trials, such as a phase I clinical trial of Uzanserti (5) for the treatment of relapsed diffuse large B-cell lymphoma that has been completed. The current focus encompasses the structural and biological characterization of PIM, ongoing research progress on small-molecule inhibitors undergoing clinical trials, and evaluation analysis of persisting challenges in this field. Additionally, the design and discovery of small-molecule inhibitors targeting PIM in recent years have been explored, with a particular emphasis on medicinal chemistry, aiming to provide valuable insights for the future development of PIM inhibitors. ■ SIGNIFICANCEA concise summary of research in the field of PIM inhibition for cancer, with a focus on medicinal chemistry, is presented. An analysis of current compounds entering clinical trials highlights existing issues and provides viewpoints on potential solutions. Future prospects and recommendations for development are discussed, emphasizing the need for unique perspectives and analyses in medicinal chemistry to stimulate critical thinking, expand understanding, and advance research in this field.

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“…PIM1 is the Proviral Integration of Molony murine leukemia virus-1 (52). Largely known for its role in solid-tumor and hematologic malignancies (52), it has been studied, albeit to a lesser extent, in Alzheimer's Disease. One study investigated the role of PIM1 in the 3xTg-AD mouse model (53).…”

Section: The Overrepresented Kinasesmentioning

confidence: 99%

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

Henkel

Joyce

Shedroff

et al. 2022

Preprint

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Neurons and astrocytes derived from Alzheimers Disease (AD) patient induced pluripotent stem cells are an evolving technology used to study the pathogenesis and etiology of AD. As the utility of mouse models of AD are increasingly coming into questions, using iPSC technology may offer an opportunity to study this disease with human substrates. Herein, we using a hypothesis generating platform, the PamGene12 Kinome Array, to identify core protein kinases in neurons and astrocytes derived from familial AD patient iPSCs. We identified five core protein kinases in these cells and examined the pathways in which they are enriched. Importantly, we complement our findings using an in-silico approach with postmortem AD brain datasets. While these protein kinases have been conceptualized in the context of traditional AD pathology, they have not been explored in the context of aberrant signaling in the pathophysiology of the disease.

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A systematic review on active sites and functions of PIM-1 protein

Cited by 13 publications

References 111 publications

Precise Interference of RNA–Protein Interaction by CRISPR-Cas13-Mediated Peptide Competition

Precise Interference of RNA–Protein Interaction by CRISPR-Cas13-Mediated Peptide Competition

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

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