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Acta Physiologica (Oxford, England) Jul 2024With a focus on the discrepancy between preclinical and clinical findings, this review will gather comprehensive information about the effects of calcineurin inhibitors... (Review)
Review
AIMS
With a focus on the discrepancy between preclinical and clinical findings, this review will gather comprehensive information about the effects of calcineurin inhibitors (CNI) on cognitive function and related brain pathology from in vitro, in vivo, and clinical studies. We also summarize the potential mechanisms that underlie the pathways related to CNI-induced cognitive impairment.
METHODS
We systematically searched articles in PubMed using keywords 'calcineurin inhibitor*' and 'cognition' to identify related articles, which the final list pertaining to underlying mechanisms of CNI on cognition.
RESULTS
Several studies have reported an association between calcineurin and the neuropathology of Alzheimer's disease (AD). AD is the most common neurocognitive disorder associated with amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive impairment. CNI, including tacrolimus and cyclosporin A, are commonly prescribed for patients with transplantation of solid organs such as kidney, liver, or heart, those drugs are currently being used as long-term immunosuppressive therapy. Although preclinical models emphasize the favorable effects of CNI on the restoration of brain pathology due to the impacts of calcineurin on the alleviation of amyloid-beta deposition and tau hyperphosphorylation, or rescuing synaptic and mitochondrial functions, treatment-related neurotoxicity, resulting in cognitive dysfunctions has been observed in clinical settings of patients who received CNI.
CONCLUSION
Inconsistent results of CNI on cognition from clinical studies have been observed due to impairment of the blood-brain barrier, neuroinflammation mediated by reactive oxygen species, and alteration in mitochondrial fission, and extended research is required to confirm its promising use in cognitive impairment.
Topics: Humans; Calcineurin Inhibitors; Animals; Cognition; Cognitive Dysfunction; Brain; Calcineurin; Alzheimer Disease; Immunosuppressive Agents
PubMed: 38747643
DOI: 10.1111/apha.14161 -
Trends in Biochemical Sciences Aug 2023Dynamic protein phosphorylation and dephosphorylation are essential regulatory mechanisms that ensure proper cellular signaling and biological functions. Deregulation of... (Review)
Review
Dynamic protein phosphorylation and dephosphorylation are essential regulatory mechanisms that ensure proper cellular signaling and biological functions. Deregulation of either reaction has been implicated in several human diseases. Here, we focus on the mechanisms that govern the specificity of the dephosphorylation reaction. Most cellular serine/threonine dephosphorylation is catalyzed by 13 highly conserved phosphoprotein phosphatase (PPP) catalytic subunits, which form hundreds of holoenzymes by binding to regulatory and scaffolding subunits. PPP holoenzymes recognize phosphorylation site consensus motifs and interact with short linear motifs (SLiMs) or structural elements distal to the phosphorylation site. We review recent advances in understanding the mechanisms of PPP site-specific dephosphorylation preference and substrate recruitment and highlight examples of their interplay in the regulation of cell division.
Topics: Humans; Phosphorylation; Phosphoprotein Phosphatases; Catalytic Domain; Holoenzymes; Substrate Specificity
PubMed: 37173206
DOI: 10.1016/j.tibs.2023.04.004 -
Oncogene Dec 2023KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical...
KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.
Topics: Child; Humans; Fingolimod Hydrochloride; Gene Expression Profiling; Leukemia, Myeloid, Acute; Myeloid-Lymphoid Leukemia Protein; Proteomics; Protein Phosphatase 2
PubMed: 37891368
DOI: 10.1038/s41388-023-02840-1 -
Blood Cancer Journal Jul 2023The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK...
The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that ruxolitinib induced autophagy in JAK2 cell lines and primary MPN patient cells through the activation of protein phosphatase 2A (PP2A). Inhibition of autophagy or PP2A activity along with ruxolitinib treatment reduced proliferation and increased the death of JAK2 cells. Accordingly, proliferation and clonogenic potential of JAK2-driven primary MPN patient cells, but not of normal hematopoietic cells, were markedly impaired by ruxolitinib treatment with autophagy or PP2A inhibitor. Finally, preventing ruxolitinib-induced autophagy with a novel potent autophagy inhibitor Lys05 improved leukemia burden reduction and significantly prolonged the mice's overall survival compared with ruxolitinib alone. This study demonstrates that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2 MPN cells and improve MPN patient care.
Topics: Mice; Animals; Janus Kinase 2; Protein Phosphatase 2; Myeloproliferative Disorders; Neoplasms; Autophagy; Mutation
PubMed: 37423955
DOI: 10.1038/s41408-023-00875-x -
Biochimica Et Biophysica Acta.... Aug 2023Adaptability to intracellular or extracellular cues is essential for maintaining cellular homeostasis. Metabolic signals intricately control the morphology and functions...
Adaptability to intracellular or extracellular cues is essential for maintaining cellular homeostasis. Metabolic signals intricately control the morphology and functions of mitochondria by regulating bioenergetics and metabolism. Here, we describe the involvement of PHLPP1, a Ser/Thr phosphatase, in mitochondrial homeostasis. Microscopic analysis showed the enhanced globular structure of mitochondria in PHLPP1-depleted HEK 293T and C2C12 cells, while forced expression of PHLPP1 promoted mitochondrial tubularity. We show that PHLPP1 promoted pro-fusion markers MFN2 and p-DRP1 levels using over-expression and knockdown strategies. Contrastingly, PHLPP1 induced mitochondrial fragmentation by augmenting pro-fission markers, t-DRP1 and pDrp1 upon mitochondrial stress. At the molecular level, PHLPP1 interacted with and caused dephosphorylation of calcineurin, a p-DRP1 phosphatase, under basal conditions. Likewise, PHLPP1 dimerized with PINK1 under basal conditions. However, the interaction of PHLPP1 with both calcineurin and PINK1 was impaired upon CCCP and oligomycin-induced mitochondrial stress. Interestingly, upon mitochondrial membrane depolarization, PHLPP1 promoted PINK1 stabilization and parkin recruitment to mitochondria, and thereby activated the mitophagy machinery providing a molecular explanation for the dual effects of PHLPP1 on mitochondria under different conditions. Consistent with our in-vitro findings, depletion of phlp-2, ortholog of PHLPP1 in C. elegans, led to mitochondrial fission under basal conditions, extended the lifespan of the worms, and enhanced survival of worms subjected to paraquat-induced oxidative stress.
Topics: Animals; Caenorhabditis elegans; Calcineurin; Longevity; Protein Kinases; Ubiquitin-Protein Ligases; HEK293 Cells; Humans; Mice
PubMed: 37060964
DOI: 10.1016/j.bbadis.2023.166718 -
Cancer Letters Aug 2023Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic tumor microenvironment (TME), which aids tumor progression, drug resistance, and immune evasion....
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic tumor microenvironment (TME), which aids tumor progression, drug resistance, and immune evasion. Dual-specificity phosphatase 2 (DUSP2), a member of the mitogen-activated protein kinase phosphatase family, regulates pancreatic cancer metastasis. However, its role in the hypoxic TME in PDAC remains unknown. We explored the role of DUSP2 by simulating the hypoxic TME. DUSP2 significantly promoted apoptosis in PDAC both in vitro and in vivo, mainly through AKT1 rather than ERK1/2. Mechanistically, DUSP2 competed with AKT1 to bind to casein kinase 2 alpha 1 (CSNK2A1) and inhibited the phosphorylation of AKT1, which plays a crucial role in apoptosis resistance. Interestingly, aberrant activation of AKT1 resulted in an increase in the ubiquitin E3 ligase tripartite motif-containing 21 (TRIM21), which binds to and mediates the ubiquitination-dependent proteasomal degradation of DUSP2. Overall, we identified CSNK2A1 as a novel binding partner of DUSP2 that promotes PDAC apoptosis through CSN2KA1/AKT1 in an ERK1/2-independent manner. Activation of AKT1 also mediated proteasomal degradation of DUSP2 via the AKT1/TRIM21 positive feedback loop. We propose increasing the level of DUSP2 as a potential therapeutic strategy for PDAC.
Topics: Humans; Dual Specificity Phosphatase 2; Pancreatic Neoplasms; Hypoxia; Carcinoma, Pancreatic Ductal; Apoptosis; Cell Line, Tumor; Tumor Microenvironment; Proto-Oncogene Proteins c-akt
PubMed: 37390887
DOI: 10.1016/j.canlet.2023.216288 -
Clinical and Translational Medicine Nov 2023Colorectal cancer (CRC) is a complex, multistep disease that arises from the interplay genetic mutations and epigenetic alterations. The histone H3K36...
BACKGOUND
Colorectal cancer (CRC) is a complex, multistep disease that arises from the interplay genetic mutations and epigenetic alterations. The histone H3K36 trimethyltransferase SET domain-containing 2 (SETD2), as an epigenetic signalling molecule, has a 5% mutation rate in CRC. SETD2 expression is decreased in the development of human CRC and mice treated with Azoxymethane /Dextran sodium sulfate (AOM/DSS). Loss of SETD2 promoted CRC development. SMAD Family member 4 (SMAD4) has a 14% mutation rate in CRC, and SMAD4 ablation leads to CRC. The co-mutation of SETD2 and SMAD4 predicted advanced CRC. However, little is known on the potential synergistic effect of SETD2 and SMAD4.
METHODS
CRC tissues from mice and SW620 cells were used as research subjects. Clinical databases of CRC patients were analyzed to investigate the association between SETD2 and SMAD4. SETD2 and SMAD4 double-knockout mice were established to further investigate the role of SETD2 in SMAD4-deficient CRC. The intestinal epithelial cells (IECs) were isolated for RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) to explore the mechanism and the key molecules resulting in CRC. Molecular and cellular experiments were conducted to analyze the role of SETD2 in SMAD4-deficient CRC. Finally, rescue experiments were performed to confirm the molecular mechanism of SETD2 in the development of SMAD4-dificient CRC.
RESULTS
The deletion of SETD2 promotes the malignant progression of SMAD4-deficient CRC. Smad4 ; Setd2 mice developed a more severe CRC phenotype after AOM/DSS induction, with a larger tumour size and a more vigorous epithelial proliferation rate. Further mechanistic findings revealed that the loss of SETD2 resulted in the down-regulation of DUSP7, which is involved in the inhibition of the RAS/ERK signalling pathway. Finally, the ERK1/2 inhibitor SCH772984 significantly attenuated the progression of CRC in Smad4 ;Setd2 mice, and overexpression of DUSP7 significantly inhibited the proliferation rates of SETD2 ; SMAD4 SW620 cells.
CONCLUSIONS
Our results demonstrated that SETD2 inhibits the RAS/ERK signaling pathway by facilitating the transcription of DUSP7 in SMAD4-deficient CRC, which could provide a potential therapeutic target for the treatment of advanced CRC.
Topics: Animals; Humans; Mice; Colorectal Neoplasms; Down-Regulation; Dual-Specificity Phosphatases; Epithelial Cells; Histone-Lysine N-Methyltransferase; Signal Transduction; Smad4 Protein
PubMed: 37962020
DOI: 10.1002/ctm2.1475 -
Cellular Signalling Sep 2023Chronic epithelial defects of the cornea, which are usually associated with severe dry eye disease, diabetes mellitus, chemical injuries or neurotrophic keratitis, as... (Review)
Review
Chronic epithelial defects of the cornea, which are usually associated with severe dry eye disease, diabetes mellitus, chemical injuries or neurotrophic keratitis, as well as aging, are an unmet clinical need. CDGSH Iron Sulfur Domain 2 (CISD2) is the causative gene for Wolfram syndrome 2 (WFS2; MIM 604928). CISD2 protein is significantly decreased in the corneal epithelium of patients with various corneal epithelial diseases. Here we summarize the most updated publications and discuss the central role of CISD2 in corneal repair, as well as providing new results describing how targeting Ca-dependent pathways can improve corneal epithelial regeneration. This review mainly focuses on the following topics. Firstly, an overview of the cornea and of corneal epithelial wound healing. The key players involved in this process, such as Ca, various growth factors/cytokines, extracellular matrix remodeling, focal adhesions and proteinases, are briefly discussed. Secondly, it is well known that CISD2 plays an essential role in corneal epithelial regeneration via the maintenance of intracellular Ca homeostasis. CISD2 deficiency dysregulates cytosolic Ca, impairs cell proliferation and migration, decreases mitochondrial function and increases oxidative stress. As a consequence, these abnormalities bring about poor epithelial wound healing and this, in turn, will lead to persistent corneal regeneration and limbal progenitor cell exhaustion. Thirdly, CISD2 deficiency induces three distinct Ca-dependent pathways, namely the calcineurin, CaMKII and PKCα signaling pathways. Intriguingly, inhibition of each of the Ca-dependent pathways seems to reverse cytosolic Ca dysregulation and restore cell migration during corneal wound healing. Notably, cyclosporin, an inhibitor of calcineurin, appears to have a dual effect on both inflammatory and corneal epithelial cells. Finally, corneal transcriptomic analyses have revealed that there are six major functional groupings of differential expression genes when CISD2 deficiency is present: (1) inflammation and cell death; (2) cell proliferation, migration and differentiation; (3) cell adhesion, junction and interaction; (4) Ca homeostasis; (5) wound healing and extracellular matrix; and (6) oxidative stress and aging. This review highlights the importance of CISD2 in corneal epithelial regeneration and identifies the potential of repurposing venerable FDA-approved drugs that target Ca-dependent pathways for new uses, namely treating chronic epithelial defects of the cornea.
Topics: Humans; Calcineurin; Cornea; Epithelium, Corneal; Signal Transduction; Wound Healing
PubMed: 37315750
DOI: 10.1016/j.cellsig.2023.110755 -
JCI Insight Jul 2023The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic...
The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium-stimulated (K+-stimulated) expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomics analysis identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), as a target for Cn-mediated dephosphorylation. Deletion of NFATC4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATC4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATC4 directly regulated CYP11B2 expression. Thus, Cn controls aldosterone production via the Cn/NFATC4 pathway. Inhibition of Cn/NFATC4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus, and the Cn/NFATC4 pathway may provide novel molecular targets to treat primary aldosteronism.
Topics: Animals; Humans; Mice; Aldosterone; Calcineurin; Cytochrome P-450 CYP11B2; Hyperkalemia; NFATC Transcription Factors; Tacrolimus
PubMed: 37310791
DOI: 10.1172/jci.insight.157027 -
Medicina (Kaunas, Lithuania) Aug 2023New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence... (Review)
Review
New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability. Therefore, chemical restoration of PP2A may represent a novel treatment for these diseases. This review outlines the potential impact of reduced PP2A activity in pulmonary diseases, endogenous and exogenous inhibitors of PP2A, details the possible PP2A-dependent mechanisms observed in these conditions, and outlines potential therapeutic strategies for treatment. Substantial medicinal chemistry efforts are underway to develop therapeutics targeting PP2A activity. The development of specific activators of PP2A that selectively target PP2A holoenzymes could improve our understanding of the function of PP2A in pulmonary diseases. This may lead to the development of therapeutics for restoring normal PP2A responses within the lung.
Topics: Humans; Protein Phosphatase 2; Lung Neoplasms; Pulmonary Disease, Chronic Obstructive; Asthma; Disease Progression
PubMed: 37763671
DOI: 10.3390/medicina59091552