UVRAG: A New Player in Autophagy and Tumor Cell Growth

Liang, Chengyu; Feng, Pinghui; Ku, Bonsu; Oh, Byung‐Ha; Jung, Jae U.

doi:10.4161/auto.3437

Cited by 60 publications

(51 citation statements)

References 15 publications

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“…146 Mutation of UVRAG is frequently observed in various human cancers and may be responsible for the etiology of these cancers. [147][148][149][150] UVRAG is critical for DNA repair and chromosomal stability, especially in response to radiation. [151][152][153] Using GST affinity isolation, UVRAG was identified as a binding partner of BECN1-PIK3C3, which directly interacts with BECN1 via its CCD.…”

Section: Regulation Of Autophagy By Pik3c3 Via Atg14mentioning

confidence: 99%

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

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Section: Regulation Of Autophagy By Pik3c3 Via Atg14mentioning

confidence: 99%

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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“…UVRAG, the other target of miR-33a, has been reported as regulating autophagy (27) and chromosome stability (28,29) and acting as a tumor suppressor because allelic mutation of UVRAG was found at high frequencies in human colon cancers and its ectopic expression in a colon cancer cell line resulted in decreased proliferation and xenograft tumor formation (30). We did not detect any alteration in the ratio of LC3 I/II in GICs or non-GICs where the level of miR-33a was manipulated (data not shown), indicating that miR-33a would not affect autophagy in the glioma cells.…”

Section: Overexpression Of Mir-33a Rendered Cd133mentioning

confidence: 99%

miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways

Wang¹,

Sun²,

Hu³

et al. 2014

J. Clin. Invest.

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“…The process of formation of active phagophore (nucleation) requires the collective action of a few complexes (Figure 2.1): Atg1 complex, class III PI3K complex (including phosphatidyl inositol 3-phosphate kinase class III defined also as Vps34, core activator of the Vps34 PI3 kinase complex known as Vps15, enhancer of autophagosome formation Atg14 and Vps30/Atg6 orthologue Beclin1 the core subunits, bcl2-interacting protein), mAtg9/AtgL1 (Atg9 orthologue in mammalian cells), Ambra 1 and UVRAG (Ultraviolet irradiation resistance-associated gene) which is a positive regulator of Vps34-Beclin1 complex [49][50][51][52][53][54][55][56]. Many Atg's have been identified in yeast.…”

Section: Autophagy Signal Transduction and Corresponding Morphologicamentioning

confidence: 99%

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Wójcik

2014

Folia Histochem Cytobiol.

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Abstract:The Ubiquitin-Proteasomes System (UPS) and autophagy, two main intracellular protein degradation pathways within the eukaryotic cells which were originally regarded as rather independent, seem to be very closely related. Proteasome inhibitors, including the multipathway inhibitor bortezomib, are drawing increased attention for their therapeutic potential in the treatment of chronic inflammation and cancer, especially tumours with a high degree of malignancy. The over-activation of autophagy induces cell death and may act as a powerful tumour-suppressing mechanism. However, autophagy, serving as an important mechanism to generate nutrients in time of cellular stresses, may directly contribute to the survival of cells treated with proteasome inhibitors, and in consequence, may decrease the effectiveness of therapy. Results of studies performed on several cancer cell lines demonstrated synergy between proteasome inhibitors and autophagy inhibitors. Those results became the base for ongoing clinical trials investigating autophagy inhibition in combination with anti-cancer therapies, including bortezomib. This review provides summary of the latest data on the functioning of the UPS and the mechanisms of autophagy. The new insights describing the main pathways of autophagy activation in response to UPS inhibition related to: (i) Unfolded Protein Response, (ii) PI3K/Akt/mTOR pathway, and (iii) formation of aggresomes, are discussed. It is concluded that concomitant inhibition of the two main cellular protein degradation systems may provide new therapeutic modalities for cancer treatment.

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UVRAG: A New Player in Autophagy and Tumor Cell Growth

Cited by 60 publications

References 15 publications

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

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