<scp>SET</scp> alpha and <scp>SET</scp> beta <scp>mRNA</scp> isoforms in chronic lymphocytic leukaemia

Brander, Danielle M.; Friedman, Daphne R.; Volkheimer, Alicia D.; Christensen, Dale J.; Rassenti, Laura Z.; Kipps, Thomas J.; Guadalupe, Eross; Chen, You‐Wei; Zhang, Dadong; Wang, Xi; Davis, Carter T.; Owzar, Kouros; Weinberg, J. Brice

doi:10.1111/bjh.15677

Cited by 16 publications

(4 citation statements)

References 39 publications

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“…These forms differ in the first exons and they have in common the sequences from exon 5 to exon 11. Among these, two SET isoforms, α and β, have been identified in CLL and NHL, with increased SETα isoform correlating with CLL disease severity [ 107 , 108 ]. This may suggest that alternative splicing of SET mRNA may be an important, yet unexplored oncogenic mechanism.…”

Section: Set Is Dysregulated In Cancermentioning

confidence: 99%

Thirty years of SET/TAF1β/I2PP2A: from the identification of the biological functions to its implications in cancer and Alzheimer’s disease

Mambro

Esposito

2022

Bioscience Reports

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The gene encoding for the protein SET was identified for the first time thirty years ago as part of a chromosomal translocation in a patient affected by leukemia. Since then, accumulating evidence have linked over -expression of SET, aberrant SET splicing, and cellular localisation to cancer progression and development of neurodegenerative tauopathies such as Alzheimer’s disease. Molecular biology tools, such as targeted genetic deletion, and pharmacological approaches based on SET antagonist peptides, have contributed to unveil the molecular functions of SET and its implications in human pathogenesis. In this review we provide an overview of the functions of SET as inhibitor of histone and non-histone protein acetylation and as a potent endogenous inhibitor of Serine-Threonine phosphatase PP2A. We discuss the role of SET in multiple cellular processes, including chromatin remodelling and gene transcription, DNA repair, oxidative stress, cell cycle, apoptosis cell migration and differentiation. We review the molecular mechanisms linking SET dysregulation to tumorigenesis and discuss how SET commits neurons to progressive cell death in Alzheimer’s disease, highlighting the rationale of exploiting SET as a therapeutic target for cancer and neurodegenerative tauopathies.

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Section: Set Is Dysregulated In Cancermentioning

confidence: 99%

Thirty years of SET/TAF1β/I2PP2A: from the identification of the biological functions to its implications in cancer and Alzheimer’s disease

Mambro

Esposito

2022

Bioscience Reports

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“…We then determined how SK2 regulates PP2A expression. The SET oncogene is a physiological inhibitor of PP2A, and there are two alternatively spliced SET isoforms: SET alpha and SET beta [ 49 ]. SET oncoproteins participate in cancer progression by affecting multiple cellular processes, including the control of the cell cycle, gene transcription, apoptosis, cell migration, and epigenetic regulation.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma

Fan

Feinberg

et al. 2023

Current Oncology

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Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein–protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.

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“…It remains unclear why SET KD affects multiple cellular signaling only in HM-POS, even though SET protein levels were almost same in both the cell lines. In humans, 2 highly homological SET isoforms (SETα and SETβ) exists and high expression ratio of SETα/SETβ is observed to be associated with poor prognosis of chronic lymphocytic leukemia patient [3]. We have previously reported in human gastric cancer cell lines that SET KD-induced suppression of tumorigenic potential was rescued by SETα, but not by SETβ [9].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of an anti-cancer strategy targeting SET in canine osteosarcoma

Tsuji

Nakagawa

Sato

2019

The Journal of Veterinary Medical Science

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Osteosarcoma (OSA) is the most common bone tumor in dogs. Protein phosphatase 2A (PP2A), an evolutionary conserved serine/threonine protein phosphatase, is a crucial tumor suppressor. SET is a PP2A inhibitory protein that directly interacts with PP2A and suppresses its phosphatase activity. SET has been reported as a contributor of wide range of human and dog tumor malignancies. However, the role of SET in canine OSA (cOSA) remains unknown. In this study, we investigated the role of SET in cOSA by using 2 cOSA cell lines: POS (primary origin) and HM-POS (metastatic origin). Knockdown (KD) of SET expression was noted to slightly suppress POS cell proliferation only. Furthermore, SET KD effectively suppressed colony formation ability of both POS and HM-POS cells. SET KD was observed to repress ERK1/2, mTOR, E2F1, and NF-κB signaling in HM-POS cells, whereas it inhibited only ERK1/2 signaling in POS. Further, it was observed that SET-targeting drug, FTY720, exerted anti-cancer effects in both POS and HM-POS cells. Moreover, the drug also enhanced the anti-cancer effect of cisplatin. The data suggested that a combination therapy, based on SET targeting drugs and cisplatin, could be a potent strategy for cOSA.KEY WORDS: canine, osteosarcoma, protein phosphatase 2A (PP2A), SET Osteosarcoma (OSA) is a predominant bone tumor diagnosis in dogs. Although, any dog could potentially develop OSA, but dog breeds with body weight above 40 kg are at an increased risk of developing OSA [16,23]. Surgery, limb amputation and limb salvage/sparing, constitutes the first choice of treatment, however, more than 90% of the patients possess micro-metastasis [16,23]. Therefore, adjuvant and non-adjuvant chemotherapy is important to improve the survival rate. In canine OSA (cOSA), adjuvant chemotherapy with cisplatin, carboplatin, or doxorubicin have been associated with increased survival rates over amputation alone [1,20]. OSA is a rare cancer in humans, whereas its incidence rate in dogs is 27-times higher [22], suggesting cOSA as a good model for human disease. The standard adjuvant chemotherapeutic approach in human OSA comprises of a combination of cisplatin, methotrexate, and doxorubicin, and has remained relatively unaltered for years [25,26]. Prognosis in both the species is poor and the survival rate has not improved in decades. Therefore, establishment of novel anti-cancer drugs is urgently required.Protein phosphatase 2A (PP2A) is an evolutionally conserved serine/threonine phosphatase that suppresses the activity of multiple intracellular signals such as Akt, ERK1/2, and mTOR signaling which regulates cancer cell growth, stemness, and survival [12,18,19]. PP2A is reported to negatively regulate the activity of transcription factors such as c-Myc, E2F1, and NF-κB, that mediates tumor cell stemness and the cell cycle [9,12,19]. Inhibition of PP2A activity is required for tumor transformation and increased expression of endogenous PP2A inhibitory proteins (such as SET, CIP2A, and PME-1) contributes to lower PP2A activity in cance...

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SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia

Cited by 16 publications

References 39 publications

Thirty years of SET/TAF1β/I2PP2A: from the identification of the biological functions to its implications in cancer and Alzheimer’s disease

Thirty years of SET/TAF1β/I2PP2A: from the identification of the biological functions to its implications in cancer and Alzheimer’s disease

Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma

Efficacy of an anti-cancer strategy targeting SET in canine osteosarcoma

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