IBtkα Activates the β-Catenin-Dependent Transcription of MYC through Ubiquitylation and Proteasomal Degradation of GSK3β in Cancerous B Cells

Vecchio, Eleonora; Nisticò, Nancy; Golino, Gaetanina; Iaccino, Enrico; Maisano, Domenico; Mimmi, Selena; Aloisio, Annamaria; Renna, Maurizio; Avagliano, Angelica; Arcucci, Alessandro; Fiume, Giuseppe; Quinto, Ileana

doi:10.3390/ijms23042044

Cited by 10 publications

(9 citation statements)

References 52 publications

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“…HEK-293T cells were lysated in a Ripa buffer assay (Radioimmunoprecipitation assay) [ 41 , 42 , 43 ] and incubated overnight with 1 μg of anti-FTH1 antibody or with non-immune serum at 4 °C and then incubated for 1h at 4 °C with Protein A/G plus-agarose. The beads were collected by centrifugation, washed four times with lysis buffer and then loaded onto an SDS 12 % ( w / v ) polyacrylamide gel [ 44 ].…”

Section: Methodsmentioning

confidence: 99%

Ferritin Heavy Chain Binds Peroxiredoxin 6 and Inhibits Cell Proliferation and Migration

Sanzo

Cozzolino²,

Battaglia³

et al. 2022

IJMS

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The H Ferritin subunit (FTH1), as well as regulating the homeostasis of intracellular iron, is involved in complex pathways that might promote or inhibit carcinogenesis. This function may be mediated by its ability to interact with different molecules. To gain insight into the FTH1 interacting molecules, we analyzed its interactome in HEK293T cells. Fifty-one proteins have been identified, and among them, we focused our attention on a member of the peroxiredoxin family (PRDX6), an antioxidant enzyme that plays an important role in cell proliferation and in malignancy development. The FTH1/PRDX6 interaction was further supported by co-immunoprecipitation, in HEK293T and H460 cell lines and by means of computational methods. Next, we demonstrated that FTH1 could inhibit PRDX6-mediated proliferation and migration. Then, the results so far obtained suggested that the interaction between FTH1/PRDX6 in cancer cells might alter cell proliferation and migration, leading to a less invasive phenotype.

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Section: Methodsmentioning

confidence: 99%

Ferritin Heavy Chain Binds Peroxiredoxin 6 and Inhibits Cell Proliferation and Migration

Sanzo

Cozzolino²,

Battaglia³

et al. 2022

IJMS

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“…After incubation at 4 °C for 30 min, cells were analyzed by flow cytometer (BriCyteE6). Annexin V-based apoptotic assay was performed as previously described [38,39]. Briefly, MPP89, IST-Mes2 and HMC (1 × 10 6 ) were stained with FITC-conjugated Annexin V and propidium iodide (PI) using the Annexin V-FITC kit (Miltenyi Biotech).…”

Section: Cell Proliferation Viability Apoptosis and Cell Cycle Analysismentioning

confidence: 99%

FABP5 is a Novel Key Player in Metabolic Modulation and NF-κB dependent Inflammation driving Malignant Pleural Mesothelioma

Fiume,

Vecchio,

Gallo

et al. 2024

Preprint

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Malignant pleural mesothelioma (MPM) poses a significant challenge in oncology due to its intricate molecular and metabolic landscape, chronic inflammation, and heightened oxidative stress, which contribute to its notorious resilience and clinical complexities. Despite advancements, the precise mechanisms driving MPM carcinogenesis remain elusive, impeding therapeutic progress. Here, we explore the interplay between tumor growth dynamics, lipid metabolism, and NF-κB dysregulation in malignant pleural mesothelioma, shedding light on novel molecular mechanisms underlying its pathogenesis. Our study reveals distinctive growth dynamics in MPM cells, characterized by heightened proliferation, altered cell cycle progression, and resistance to apoptosis. Intriguingly, MPM cells exhibit increased intracellular accumulation of myristic, palmitic, and stearic acids, suggestive of augmented lipid uptake and altered biosynthesis. Notably, we identify FABP5 as key player in driving metabolic alterations and inflammation through NF-κB dysregulation in mesothelioma cells, distinguishing them from normal mesothelial cells. Silencing of FABP5 leads to significant alterations in cell dynamics, metabolism, and NF-κB activity, highlighting its potential as therapeutic target. Our findings unveil a reciprocal relationship between lipid metabolism and inflammation in MPM, providing a foundation for therapeutic strategies. Overall, this comprehensive investigation offers insights into the intricate molecular mechanisms driving MPM pathogenesis and identifies potential avenues for therapeutic intervention.

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“…However, in B-cell NHLs, GSK-3β activity could be also downmodulated via proteasomal degradation of GSK-3β itself, due to interactions with Inhibitor of Bruton’s tyrosine kinase α (IBTKα). As a consequence of GSK-3β proteolysis, the protein levels of β-catenin increase, thereby resulting in the transcriptional activation of the MYC and CCND1 target genes [ 168 ].…”

Section: Gsk-3 Signaling In B-cell Nhlsmentioning

confidence: 99%

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Martelli

Paganelli

Evangelisti

et al. 2022

Cells

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Glycogen synthase kinase-3 (GSK-3) is an evolutionarily conserved, ubiquitously expressed, multifunctional serine/threonine protein kinase involved in the regulation of a variety of physiological processes. GSK-3 comprises two isoforms (α and β) which were originally discovered in 1980 as enzymes involved in glucose metabolism via inhibitory phosphorylation of glycogen synthase. Differently from other proteins kinases, GSK-3 isoforms are constitutively active in resting cells, and their modulation mainly involves inhibition through upstream regulatory networks. In the early 1990s, GSK-3 isoforms were implicated as key players in cancer cell pathobiology. Active GSK-3 facilitates the destruction of multiple oncogenic proteins which include β-catenin and Master regulator of cell cycle entry and proliferative metabolism (c-Myc). Therefore, GSK-3 was initially considered to be a tumor suppressor. Consistently, GSK-3 is often inactivated in cancer cells through dysregulated upstream signaling pathways. However, over the past 10–15 years, a growing number of studies highlighted that in some cancer settings GSK-3 isoforms inhibit tumor suppressing pathways and therefore act as tumor promoters. In this article, we will discuss the multiple and often enigmatic roles played by GSK-3 isoforms in some chronic hematological malignancies (chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, and B-cell non-Hodgkin’s lymphomas) which are among the most common blood cancer cell types. We will also summarize possible novel strategies targeting GSK-3 for innovative therapies of these disorders.

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IBtkα Activates the β-Catenin-Dependent Transcription of MYC through Ubiquitylation and Proteasomal Degradation of GSK3β in Cancerous B Cells

Cited by 10 publications

References 52 publications

Ferritin Heavy Chain Binds Peroxiredoxin 6 and Inhibits Cell Proliferation and Migration

Ferritin Heavy Chain Binds Peroxiredoxin 6 and Inhibits Cell Proliferation and Migration

FABP5 is a Novel Key Player in Metabolic Modulation and NF-κB dependent Inflammation driving Malignant Pleural Mesothelioma

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

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