<scp>TRIM</scp>24 mediates the interaction of the retinoic acid receptor alpha with the proteasome

Carrier, Marilyn; Lutzing, Régis; Gaouar, Samia; Rochette‐Egly, Cécile

doi:10.1002/1873-3468.13033

Cited by 4 publications

(3 citation statements)

References 38 publications

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“…3d). Regardless of ATRA treatment, which stimulates the process [39], S100A3 increases RARα polyubiquitinylation and the effect is magnified by pUb-HA . This suggests that S100A3/RARα interaction inhibits constitutive and ATRA-dependent degradation of the retinoid-receptor by the proteasome.…”

Section: Resultsmentioning

confidence: 99%

S100A3 a partner protein regulating the stability/activity of RARα and PML-RARα in cellular models of breast/lung cancer and acute myeloid leukemia

et al. 2018

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All trans-retinoic acid (ATRA) is used in the treatment of acute promyelocytic leukemia (APL) and it is a promising agent also in solid tumors. The pharmacological activity of ATRA is mediated by the ligand-activated RAR and RXR transcription factors. In the present study, we define the basal and ATRA dependent RARα interactome in a RARα-overexpressing breast cancer cellular model, identifying 28 nuclear proteins. We focus our attention on the S100A3 calcium-binding protein, which interacts with RARα constitutively. In ATRA-sensitive breast cancer cells, S100A3 binds to RARα in basal conditions and binding is reduced by the retinoid. The interaction of S100A3 with RARα is direct and in lung cancer, APL and acute-myeloid-leukemia (AML) cells. In APL, S100A3 interacts not only with RARα, but also with PML-RARα. The interaction surface maps to the RARα ligand-binding domain, where the I396 residue plays a crucial role. Binding of S100A3 to RARα/PML-RARα controls the constitutive and ATRA-dependent degradation of these receptors. S100A3 knockdown decreases the amounts of RARα in breast- and lung cancer cells, inducing resistance to ATRA-dependent anti-proliferative/differentiating effects. Conversely, S100A3 knockdown in PML-RARα + APL and PML-RARα − AML cells reduces the amounts of RARα/PML-RARα and increases basal and ATRA-induced differentiation. In this cellular context, opposite effects on RARα/PML-RARα levels and ATRA-induced differentiation are observed upon S100A3 overexpression. Our results provide new insights into the molecular mechanisms controlling RARα activity and have practical implications, as S100A3 represents a novel target for rational drug combinations aimed at potentiating the activity of ATRA.

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Section: Resultsmentioning

confidence: 99%

S100A3 a partner protein regulating the stability/activity of RARα and PML-RARα in cellular models of breast/lung cancer and acute myeloid leukemia

et al. 2018

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“…In terms of the nuclear receptors, TRIM24 serves as a corepressor of RARα, which is the molecular target of ATRA. Moreover, by possessing protein-ubiquitin ligase activity, TRIM24 is involved in the proteasome-mediated degradation of the above-mentioned nuclear receptor RARα [ 57 ]. TRIM24 pharmacological targeting could provide an antileukemic effect.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Proteomics of Induced Leukemia Cell Differentiation

Novikova

Tolstova²,

Курбатов³

et al. 2022

Cells

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Studies of induced granulocytic differentiation help to reveal molecular mechanisms of cell maturation. The nuclear proteome represents a rich source of regulatory molecules, including transcription factors (TFs). It is important to have an understanding of molecular perturbations at the early stages of the differentiation processes. By applying the proteomic quantitative profiling using isobaric labeling, we found that the contents of 214, 319, 376, 426, and 391 proteins were altered at 3, 6, 9, 12, and 72 h, respectively, compared to 0 h in the HL-60 cell nuclear fraction under all-trans-retinoid acid (ATRA) treatment. From 1860 identified nuclear proteins, 231 proteins were annotated as proteins with transcription factor (TF) activity. Six TFs (RREB1, SRCAP, CCDC124, TRIM24, BRD7, and BUD31) were downregulated and three TFs EWSR1, ENO1, and FUS were upregulated at early time points (3–12 h) after ATRA treatment. Bioinformatic annotation indicates involvement of the HL-60 nuclear proteome in DNA damage recognition in the RUNX1-triggered pathway, and in the p53-regulation pathway. By applying scheduled multiple reaction monitoring using stable isotopically labeled peptide standards (MRM/SIS), we found a persistent increase in the content of the following proteins: PRAM1, CEPBP, RBPJ, and HIC1 in the HL-60 cell nuclear fraction during ATRA-induced granulocytic differentiation. In the case of STAT1, CASP3, PARP1, and PRKDC proteins, a transient increase in their content was observed at early time points (3–12 h) after the ATRA treatment. Obtained data on nuclear proteome composition and dynamics during granulocytic differentiation could be beneficial for the development of new treatment approaches for leukemias with the mutated p53 gene.

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“…Interestingly, all three genes coding for RA receptors are induced by RA creating a feedforward loop which, in theory, could serve to coordinate the timing of ligand synthesis with RAR expression [ 72 , 258 , 259 , 260 , 261 , 262 , 263 ]. The termination of RAR-signaling is a poorly understood event, however, there is evidence that RA binding induces ubiquitin-mediated degradation of RAR via the proteasome [ 264 , 265 , 266 , 267 ].…”

Section: Cellular Fate Of Ra and Ra Breakdownmentioning

confidence: 99%

Mechanisms of Feedback Regulation of Vitamin A Metabolism

2022

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Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity. For this reason, intricate feedback mechanisms have evolved to allow tissues to generate appropriate levels of active retinoid metabolites despite variations in the level and format, or in the absorption and conversion efficiency of dietary vitamin A precursors. Here, we review basic mechanisms that govern vitamin A signaling and metabolism, and we focus on retinoic acid-controlled feedback mechanisms that contribute to vitamin A homeostasis. Several approaches to investigate mechanistic details of the vitamin A homeostatic regulation using genomic, gene editing, and chromatin capture technologies are also discussed.

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TRIM24 mediates the interaction of the retinoic acid receptor alpha with the proteasome

Cited by 4 publications

References 38 publications

S100A3 a partner protein regulating the stability/activity of RARα and PML-RARα in cellular models of breast/lung cancer and acute myeloid leukemia

S100A3 a partner protein regulating the stability/activity of RARα and PML-RARα in cellular models of breast/lung cancer and acute myeloid leukemia

Nuclear Proteomics of Induced Leukemia Cell Differentiation

Mechanisms of Feedback Regulation of Vitamin A Metabolism

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