Intracellular protein degradation: From a vague idea through the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting

Ciechanover, Aaron

doi:10.1016/j.bmc.2013.01.056

Cited by 103 publications

(72 citation statements)

References 82 publications

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“…have previously shown that cIAP2 is cleaved by the mitochondrial serine protease Omi/HtrA2 during apoptosis [56]. Given the predominant mitochondrial localization of MCC, it is likely that the ER stress-induced decrease of MCC protein levels may be mediated through selective mitochondrial autophagy or proteasome-dependent degradation [57–59]. Together, our data demonstrated that MCC exhibits a primary mitochondrial localization in human MM cells, and that MCC protein levels are down-regulated by ER stress and apoptosis induction in malignant B cells.…”

Section: Resultsmentioning

confidence: 99%

Mutated in colorectal cancer (MCC) is a novel oncogene in B lymphocytes

Edwards¹,

Baron²,

Moore³

et al. 2014

J Hematol Oncol

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BackgroundIdentification of novel genetic risk factors is imperative for a better understanding of B lymphomagenesis and for the development of novel therapeutic strategies. TRAF3, a critical regulator of B cell survival, was recently recognized as a tumor suppressor gene in B lymphocytes. The present study aimed to identify novel oncogenes involved in malignant transformation of TRAF3-deficient B cells.MethodsWe used microarray analysis to identify genes differentially expressed in TRAF3−/− mouse splenic B lymphomas. We employed lentiviral vector-mediated knockdown or overexpression to manipulate gene expression in human multiple myeloma (MM) cell lines. We analyzed cell apoptosis and proliferation using flow cytometry, and performed biochemical studies to investigate signaling mechanisms. To delineate protein-protein interactions, we applied affinity purification followed by mass spectrometry-based sequencing.ResultsWe identified mutated in colorectal cancer (MCC) as a gene strikingly up-regulated in TRAF3-deficient mouse B lymphomas and human MM cell lines. Aberrant up-regulation of MCC also occurs in a variety of primary human B cell malignancies, including non-Hodgkin lymphoma (NHL) and MM. In contrast, MCC expression was not detected in normal or premalignant TRAF3−/− B cells even after treatment with B cell stimuli, suggesting that aberrant up-regulation of MCC is specifically associated with malignant transformation of B cells. In elucidating the functional roles of MCC in malignant B cells, we found that lentiviral shRNA vector-mediated knockdown of MCC induced apoptosis and inhibited proliferation in human MM cells. Experiments of knockdown and overexpression of MCC allowed us to identify several downstream targets of MCC in human MM cells, including phospho-ERK, c-Myc, p27, cyclin B1, Mcl-1, caspases 8 and 3. Furthermore, we identified 365 proteins (including 326 novel MCC-interactors) in the MCC interactome, among which PARP1 and PHB2 were two hubs of MCC signaling pathways in human MM cells.ConclusionsOur results indicate that in sharp contrast to its tumor suppressive role in colorectal cancer, MCC functions as an oncogene in B cells. Our findings suggest that MCC may serve as a diagnostic marker and therapeutic target in B cell malignancies, including NHL and MM.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0056-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Mutated in colorectal cancer (MCC) is a novel oncogene in B lymphocytes

Edwards¹,

Baron²,

Moore³

et al. 2014

J Hematol Oncol

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“…9c). The 26S proteasome is assembled from components, including the 20S catalytic core and the 19S regulatory particle [10][11][12] . Scl1 TAP (core subunit) and Rpn6 TAP (regulatory subunit) were used to purify the 20S core (represented by Pre10) and the 26S proteasome that comprised the core and regulatory particles (represented by Rpt1 and Rpt5) (Fig.…”

Section: Letter Researchmentioning

confidence: 99%

“…The ubiquitin-proteasome system (UPS) [9][10][11][12] is involved in the degradation of MIA substrate proteins 8,13 . Abundance of many proteins involved in the UPS did not change in mia40-4int S , including the core proteasomal subunits (Supplementary Table 3 and Extended Data Fig.…”

mentioning

confidence: 99%

Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol

Wróbel

Topf

Brągoszewski

et al. 2015

Nature

375

429

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Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.

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“…Proteasomes are tubular multi-molecular complexes, the mature form called the 26S proteasome, and are composed of one 20S core and two 19S regulatory units. 197 Through their role in protein degradation, proteasomes are implicated in cellular processes, including apoptosis, the removal of various misfolded and immature proteins, and the production of peptides for presentation by MHC class I molecules. 198 The core of the 20S proteasome is comprised of four stacked rings.…”

Section: Geneticsmentioning

confidence: 99%