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

Abstract

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.

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML.

“…Given the poor outcomes of the KMT2A-R-leukemias and the relatively well characterised cellular context driving leukemogenesis, we further investigated the mechanistic role of SET in this group. As SET oncoprotein has several distinct roles depending on its subcellular localisation (22), we analysed its subcellular localisation in two KMT2A-R-cell lines (THP1 and MV411) and one KMT2A-wt cell line (K562) by nuclear/cytoplasm fractionation followed by western blot and showed that SET was relatively more abundant in the cytoplasm than in the nucleus of these cells (Fig. 1F).…”

“…SET is an oncoprotein also known as template activating factor-I-β (TAF I-β), inhibitor 2 of protein phosphatase 2A (I2PP2A) and putative histocompatibility leukocyte antigen class II-Associated Protein II (PHAPII). Originally identi ed as fusion gene in leukemia (17), it is over-expressed in several forms of solid tumors and hematological malignancies (18)(19)(20)(21)(22). In BCR::ABL + chronic myeloid leukemia (CML), the inhibitory effect of SET on SER-THR phosphatase PP2A switches the oncogenic driver kinase BCR::ABL off, highlighting its potency as a negative regulator of oncogenic cascades (18,22,23).…”

“…Originally identi ed as fusion gene in leukemia (17), it is over-expressed in several forms of solid tumors and hematological malignancies (18)(19)(20)(21)(22). In BCR::ABL + chronic myeloid leukemia (CML), the inhibitory effect of SET on SER-THR phosphatase PP2A switches the oncogenic driver kinase BCR::ABL off, highlighting its potency as a negative regulator of oncogenic cascades (18,22,23). SET has also been recognised as a prognostic marker for poor overall survival in AML (19,20), although the exact molecular mechanisms linking a SET oncoprotein pathway with aggressive AML outcomes remain still obscure.…”

Effects of Combination of Ethanol With Ritonavir, Lopinavir or Darunavir on Expression and Localization of the Er-Associated Set Protein and Infection of Hiv-1 Pseudovirus in Primary Human Cells

“…The SET protein is an endoplasmic reticulum (ER)-associated chaperone protein expressed in many types of cells and has multiple biological functions depending on cell types, cellular location, and complex formations with other protein components. 11 In leukemic cells, the SET protein functions as an endogenous inhibitor of serine-threonine phosphatase PP2A suppressing apoptosis and promoting cell survival and proliferation. 12 In Alzheimer disease, the SET protein prevents histone H1 from interacting with DNA and commits neurons to progressive cell death.…”

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML

“…SET is an oncoprotein also known as template activating factor-I-β, inhibitor 2 of Ser-Thr protein phosphatase 2A and putative histocompatibility leukocyte antigen class II-associated protein II. Originally identified as fusion gene in acute leukemia [ 20 ], it is overexpressed in several forms of solid tumors and hematological malignancies [ 21 – 26 ]. In BCR::ABL + chronic myeloid leukemia (CML), SET-mediated PP2A inactivation is essential for the self-renewal of CML leukemic stem cells [ 27 ].…”