Interaction of p53 with the CCT Complex Promotes Protein Folding and Wild-Type p53 Activity

Trinidad, Antonio G.; Müller, Patricia; Cuéllar, Jorge; Klejnot, Marta; Nobis, Max; Valpuesta, José M.; Vousden, Karen H.

doi:10.1016/j.molcel.2013.05.002

Cited by 130 publications

(120 citation statements)

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“…For example, in the case of cytoskeletal proteins, TRiC depletion ultimately causes loss of polymerization activity for actin and tubulin. For p53, TRiC depletion leads to decreased p53-protein interactions and, in the case of STAT3, it induces a decrease in its ability to be phosphorylated (22,23,35). Here we exhaustively demonstrate that TRiC is strictly required for AML1-ETO synthesis in RRLs (Fig.…”

Section: Discussionmentioning

confidence: 51%

“…Indeed, this chaperonin plays a central role in the cytosol by assisting the folding of ϳ10 -15% of all newly synthesized polypeptides (19). Furthermore, TRiC has been suggested to play a role in cancer cell development by modulating the folding and activity of client proteins involved in oncogenesis, such as the tumor suppressor proteins Von Hippel-Lindau (VHL) (20,21) and p53 (22), as well as the prooncogenic protein STAT3 (signal transducer and activator of transcription 3) (23). Of note, the expression levels of TRiC in leukemic cells are higher than in normal hematopoietic cells (24), suggesting a potential contribution of TRiC to leukemogenesis through its interactions with leukemia-causing oncoproteins.…”

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confidence: 99%

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Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO

Roh¹,

Kasembeli

Galaz-Montoya³

et al. 2016

Journal of Biological Chemistry

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AML1-ETO is the most common fusion oncoprotein causing acute myeloid leukemia (AML), a disease with a 5-year survival rate of only 24%. AML1-ETO functions as a rogue transcription factor, altering the expression of genes critical for myeloid cell development and differentiation. Currently, there are no specific therapies for AML1-ETO-positive AML. While known for decades to be the translational product of a chimeric gene created by the stable chromosome translocation t(8;21)(q22;q22), it is not known how AML1-ETO achieves its native and functional conformation or whether this process can be targeted for therapeutic benefit. Here, we show that the biosynthesis and folding of the AML1-ETO protein is facilitated by interaction with the essential eukaryotic chaperonin TRiC (or CCT). We demonstrate that a folding intermediate of AML1-ETO binds to TRiC directly, mainly through its ␤-strand rich, DNA-binding domain (AML-(1-175)), with the assistance of HSP70. Our results suggest that TRiC contributes to AML1-ETO proteostasis through specific interactions between the oncoprotein's DNA-binding domain, which may be targeted for therapeutic benefit.Acute myeloid leukemia (AML) 4 is characterized by the uncontrolled proliferation and incomplete differentiation of a malignant clone of myeloid stem or progenitor cells (1). The majority of cases can be categorized based on the stable, nonrandom chromosome translocation they contain. The most common translocation in AML is t(8;21)(q22;q22), which juxtaposes portions of two genes, AML1 and ETO, generating the fusion oncoprotein AML1-ETO (2). The AML1 gene encodes a critical transcription factor that regulates a variety of genes involved in proliferation and differentiation of many cell types, including those within the hematopoietic system (3, 4). On the other hand, the ETO (eight twenty-one) protein is a protein harboring transcriptional repressor activities (5). The DNAbinding domain of AML1 is located within the amino-terminal portion of AML1-ETO and is fused in-frame to portions of the ETO gene containing dimerization and zinc finger motifs shown to interact with nuclear receptor co-repressors such as the N-CoR (nuclear receptor co-repressor)/SMRT (silencing mediator for retinoid and thyroid receptors) complex and HDAC (histone deacetylase) (6 -8). Thus, AML1-ETO functions as a rogue transcriptional repressor, rather than as a transcriptional activator.Unfortunately, there are currently no specific treatments for AML1-ETO-positive leukemia and the prognosis for this disease remains dismal. However, it has been shown that targeting of AML1-ETO using small interfering RNAs (siRNAs) supports normal myeloid differentiation of t(8;21)-positive leukemic cells (9), which highlights AML1-ETO as a direct clinical target to treat AML. Interestingly, inhibition of heat shock protein 70/90 (HSP70/90), two major proteostasis regulators, has shown antileukemic effects in AML1-ETO-positive cells (10, 11), suggesting that AML1-ETO might rely on chaperones to fold and function properly. Howe...

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Section: Discussionmentioning

confidence: 51%

mentioning

confidence: 99%

Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO

Roh¹,

Kasembeli

Galaz-Montoya³

et al. 2016

Journal of Biological Chemistry

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“…Recently, the CCT/TRiC chaperonin complex was shown to be required for maintaining the wild-type p53 conformation (Trinidad et al 2013); mutants incapable of CCT binding promote cancer cell migration and invasion. Likewise, embryonic stem cells harboring mutant p53 were found to maintain genomic integrity by forcing the mutant p53 to adopt a wild-type conformation (Rivlin et al 2014).…”

Section: P53-dependent Migration Involves Noncanonical P53 Target Genmentioning

confidence: 99%

Down-regulation of LATS kinases alters p53 to promote cell migration

et al. 2015

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p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in nontransformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53's conformation and transcriptional output toward a state resembling cancer-associated p53 mutants and endows p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently down-regulated in breast cancer; we propose that such down-regulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.

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“…TRiC substrates include cell cycle regulators, signaling proteins, and cytoskeletal components (14,15). Furthermore, TRiC has been suggested to play a critical role in cancer cell development by modulating the folding and activity of client proteins involved in oncogenesis (16), such as the tumor suppressor proteins Von Hippel-Lindau (VHL) (17,18) and p53 (19), as well as the oncogenic protein STAT3 and AML1-ETO (12,20). Structurally, TRiC/CCT is a 1 MDa hetero-oligomeric complex composed of two rings with eight different, yet paralogous, subunits each (CCT1-CCT8) arranged in a specific order (21,22).…”

Section: Introductionmentioning

confidence: 99%

Chaperonin TRiC/CCT Recognizes Fusion Oncoprotein AML1-ETO through Subunit-Specific Interactions

Roh

Kasembeli

Galaz-Montoya

et al. 2016

Biophysical Journal

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AML1-ETO is the translational product of a chimeric gene created by the stable chromosome translocation t (8;21)(q22;q22). It causes acute myeloid leukemia (AML) by dysregulating the expression of genes critical for myeloid cell development and differentiation and recently has been reported to bind multiple subunits of the mammalian cytosolic chaperonin TRiC (or CCT), primarily through its DNA binding domain (AML1-175). Through these interactions, TRiC plays an important role in the synthesis, folding, and activity of AML1-ETO. Using single-particle cryo-electron microscopy, we demonstrate here that a folding intermediate of AML1-ETO's DNA-binding domain (AML1-175) forms a stable complex with apo-TRiC. Our structure reveals that AML1-175 associates directly with a specific subset of TRiC subunits in the open conformation.

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Interaction of p53 with the CCT Complex Promotes Protein Folding and Wild-Type p53 Activity

Cited by 130 publications

References 52 publications

Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO

Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO

Down-regulation of LATS kinases alters p53 to promote cell migration

Chaperonin TRiC/CCT Recognizes Fusion Oncoprotein AML1-ETO through Subunit-Specific Interactions

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