CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation

Puustinen, Pietri; Rytter, Anna; Mortensen, Monika; Kohonen, Pekka; Moreira, José M.A.; Jäättelä, Marja

doi:10.1083/jcb.201304012

Cited by 64 publications

(65 citation statements)

References 38 publications

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“…Puustinen and collaborators, working in cancer cells (MCF7 cells) have recently identified an inhibitory effect of CIP2A on macroautophagy, by modulating its major negative regulator, the mechanistic target of rapamycin (serine/threonine kinase) complex 1. 47,48 Despite the higher levels of CIP2A in the CMA-incompetent cells, we did not find reduced macroautophagy activity in these cells, suggesting that the effect of CIP2A on macroautophagy may be different in cancer cells and in cells undergoing transformation. However, it is interesting that contrary to most untransformed cells where blockage of CMA leads to marked upregulation of macroautophagy, we find only a discrete increase in macroautophagy levels in the CMAdefective cells in presence of MYC (Fig.…”

Section: Discussioncontrasting

confidence: 37%

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

2017

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Chaperone-mediated autophagy (CMA), a selective form of protein lysosomal degradation, is maximally activated in stress situations to ensure maintenance of cellular homeostasis. CMA activity decreases with age and in several human chronic disorders, but in contrast, in most cancer cells, CMA is upregulated and required for tumor growth. However, the role of CMA in malignant transformation remains unknown. In this study, we demonstrate that CMA inhibition in fibroblasts augments the efficiency of MYC/c-Mycdriven cellular transformation. CMA blockage contributes to the increase of total and nuclear MYC, leading to enhancement of cell proliferation and colony formation. Impaired CMA functionality accentuates tumorigenesis-related metabolic changes observed upon MYC-transformation. Although not a direct CMA substrate, we have found that CMA regulates cellular MYC levels by controlling its proteasomal degradation. CMA promotes MYC ubiquitination and degradation by regulating the degradation of C330027C09Rik/KIAA1524/CIP2A (referred to hereafter as CIP2A), responsible for MYC stabilization. Ubiquitination and proteasomal degradation of MYC requires dephosphorylation at Ser62, and CIP2A inhibits the phosphatase responsible for this dephosphorylation. Failure to degrade CIP2A upon CMA blockage leads to increased levels of phosphorylated MYC (Ser62) and to stabilization of this oncogene. We demonstrate that this phosphorylation is essential for the CMA-mediated effect, since specific mutation of this site (Ser62 to Ala62) is enough to normalize MYC levels in CMA-incompetent cells. Altogether these data demonstrate that CMA mitigates MYC oncogenic activity by promoting its proteasomal degradation and reveal a novel tumor suppressive role for CMA in nontumorigenic cells.

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Section: Discussioncontrasting

confidence: 37%

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

2017

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“…The current study reports that while pAkt (Ser473) is downregulated in cells upon CIP2A knockdown, p-mTOR (Ser2448) and the mTOR effector protein P70S6K (Thr412/389) are decreased. A previous study reported that CIP2A controls cell growth and autophagy through mTORC1 activation in MCF-7 cells (22). The results of the present study indicate that the downregulation of the Akt/mTOR/ P70S6K signaling pathway may contribute to autophagy induced by CIP2A depletion.…”

Section: A B C Discussionsupporting

confidence: 56%

“…Autophagy and apoptosis are two important self-destructive processes that serve a pivotal role in the maintenance of human health, as well as in the pathogenesis of several tumors (21,22). In the present study, CIP2A depletion significantly induced caspase-3 activation, followed by PARP cleavage in two TNBC cell lines, suggesting that CIP2A depletion induces caspase-dependent apoptosis in TNBC cells (Fig.…”

Section: A B C Discussionsupporting

confidence: 48%

Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

Feng

Guo

et al. 2016

Oncology Letters

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Abstract. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized oncoprotein which is involved in the progression of several human malignancies. The present study aimed to investigate its biological function in human triple negative breast cancer (TNBC). The expression of CIP2A in TNBC cells was examined and it was observed that CIP2A was elevated in the TNBC cell line compared with poorly invasive breast cancer cells. CIP2A depletion in TNBC cell lines inhibited proliferation, and induced apoptosis and autophagy. In addition, CIP2A depletion inhibited invasion and migration of TNBC cells. Furthermore, CIP2A depletion downregulated Akt/mTOR/P70S6K phosphorylation. These results validate the role of CIP2A as a invasion-associated oncoprotein and established CIP2A as a promising therapeutic target of TNBC.

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“…43,44 As an example, autophagy-related proteins also affect cell proliferation. 26,28,45,46 Indeed, to adapt to nutrient deprivation or other cell stresses, a simultaneous regulation of autophagy and cell growth occurs in eukaryotic organisms. First, a plethora of signaling molecules and pathways have opposite effects on cell growth and autophagy, supporting the idea that these processes might represent mutually exclusive cell fates.…”

Section: Discussionmentioning

confidence: 99%

MIR7–3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1

et al. 2017

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Macroautophagy/autophagy is a tightly regulated intracellular catabolic pathway involving the lysosomal degradation of cytoplasmic organelles and proteins to be recycled into metabolic precursors. AMBRA1 (autophagy and Beclin 1 regulator 1) has a central role in the autophagy signaling network; it acts upstream of MTORC1-dependent autophagy by stabilizing the kinase ULK1 (unc-51 like autophagy activating kinase 1) and by favoring autophagosome core complex formation. AMBRA1 also regulates the cell cycle by modulating the activity of the phosphatase PPP2/PP2A (protein phosphatase 2) and degradation of MYC. Of note, post-transcriptional regulation mediated by noncoding microRNAs (MIRNAs) contributes significantly to control autophagy. Here we describe a new role for the microRNA MIR7-3HG/MIR-7 as a potent autophagy inhibitor. Indeed, MIR7-3HG targets the 3 0 untranslated region (UTR) of AMBRA1 mRNA, inducing a decrease of both AMBRA1 mRNA and protein levels, and thus causing a block in autophagy. Furthermore, MIR7-3HG, through AMBRA1 downregulation, prevents MYC dephosphorylation, establishing a positive feedback for its own transcription. These data suggest a new and interesting role of MIR7-3HG as an antiautophagic MIRNA that may affect oncogenesis through the regulation of the tumor suppressor AMBRA1.

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CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation

Abstract: As part of a regulatory loop linking cell metabolism, growth, and proliferation, CIP2A promotes mTORC1-mediated cell growth and autophagy inhibition but is itself down-regulated by autophagy.

Cited by 64 publications

References 38 publications

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

MIR7–3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1

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