Methylation-Controlled J Protein Promotes c-Jun Degradation To Prevent ABCB1 Transporter Expression

Hatle, Ketki M.; Neveu, Wendy; Dienz, Oliver; Rymarchyk, Stacia; Barrantes, Ramiro; Hale, Sarah; Farley, Nicholas; Lounsbury, Karen M.; Bond, Jeffrey P.; Taatjes, Douglas J.; Rincón, Mercedes

doi:10.1128/mcb.01804-06

Cited by 52 publications

(66 citation statements)

References 54 publications

(43 reference statements)

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“…Ovarian and breast cancer patients exposed to continuous chemotherapy exhibited lower levels of DNAJC15 protein and enhanced drug resistance (36,37). In addition, loss of DNAJC15 has been associated with P-gp overexpression and can modulate cellular responses to altered metabolic conditions by enhancing mitochondrial respiration (38,39). Transcripts encoding the DENN/MADD domain containing 2D protein (DENND2D) were also detected in CEM but not CEM/R2 cells.…”

Section: Discussionmentioning

confidence: 92%

Rewired Metabolism in Drug-resistant Leukemia Cells

Stäubert

Bhuiyan

Lindahl

et al. 2015

Journal of Biological Chemistry

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Background: Drug resistance is a common problem in cancer chemotherapy. Results: Transcriptomic and metabolomic data show that resistant leukemia cells exhibit reduced glutamine dependence, enhanced glucose dependence, and altered fatty acid metabolism. Conclusion:The metabolism of resistant leukemia cells is fundamentally rewired. Significance: Understanding the metabolic cost of resistance can lead to novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 92%

Rewired Metabolism in Drug-resistant Leukemia Cells

Stäubert

Bhuiyan

Lindahl

et al. 2015

Journal of Biological Chemistry

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“…JC15 was documented as a protein whose epigenetic silencing regulates the response to chemotherapeutic drug treatment and in normal cells of epithelial origin (30,32,42), whereas JC19 was identified as a protein whose mutation was associated with development of DCM syndrome (24). However, both JC19 and JC15 form a stable heterodimer with that of Magmas through their J-domain with equal affinity, which like other membrane-associated J-proteins, is the minimal region required for the interaction.…”

Section: Discussionmentioning

confidence: 99%

Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase

Sinha

Srivastava

D’Silva

2016

Journal of Biological Chemistry

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Mitochondrial J-proteins play a critical role in governing Hsp70 activity and, hence, are essential for organellar protein translocation and folding. In contrast to yeast, which has a single J-protein Pam18, humans involve two J-proteins, DnaJC15 and DnaJC19, associated with contrasting cellular phenotype, to transport proteins into the mitochondria. Mutation in DnaJC19 results in dilated cardiomyopathy and ataxia syndrome, whereas expression of DnaJC15 regulates the response of cancer cells to chemotherapy. In the present study we have comparatively assessed the biochemical properties of the J-protein paralogs in relation to their association with the import channel. Both DnaJC15 and DnaJC19 formed two distinct subcomplexes with Magmas at the import channel. Knockdown analysis suggested an essential role for Magmas and DnaJC19 in organellar protein translocation and mitochondria biogenesis, whereas DnaJC15 had dispensable supportive function. The J-proteins were found to have equal affinity for Magmas and could stimulate mitochondrial Hsp70 ATPase activity by equivalent levels. Interestingly, we observed that DnaJC15 exhibits bifunctional properties. At the translocation channel, it involves conserved interactions and mechanism to translocate the precursors into mitochondria. In addition to protein transport, DnaJC15 also showed a dual role in yeast where its expression elicited enhanced sensitivity of cells to cisplatin that required the presence of a functional J-domain. The amount of DnaJC15 expressed in the cell was directly proportional to the sensitivity of cells. Our analysis indicates that the differential cellular phenotype displayed by human mitochondrial J-proteins is independent of their activity and association with Magmas at the translocation channel.In eukaryotic cells mitochondria form an essential organelle that plays a central role in cancer, apoptosis, and cytotoxic responses and maintains the overall metabolic homeostasis within the cell (1, 2). More than 98% of the human mitochondrial protein pool is nuclear-encoded and transported into the mitochondria through highly complex import machinery spanning the outer membrane, inner membrane, and the intermembrane space (2, 3). At the inner membrane, TIM23 complex forms the sole gateway for translocation of precursor proteins into the matrix, which accounts for ϳ60% of the total imported proteins (4, 5). The TIM23 complex comprises of two components: membrane-embedded Tim23 core channel and the motor component. Although the initial membrane potential dependent translocation is mediated by the Tim23-Tim17 channel, it is the overall activity of the import motor, which determines the translocation process (3, 4, 6 -10). The import motor contains mtHsp70 as its core, whose function is orchestrated by J-proteins (7,(11)(12)(13). The ADP/ATP states of Hsp70 regulate its interactions with client proteins (14, 15). However, the basal ATPase activity of Hsp70 is not sufficient to drive the reactions efficiently and, thus, requires J-proteins as cofactors ...

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“…However, Zhou et al showed that adenovirus-mediated upregulation of the low p-JNK level found in PgP( þ ) solid tumor cells increased anthracycline incorporation in these cells and reversed P-gP-related resistance, suggesting that JNK may also downregulate P-gP. 27 Although other reports in solid tumors argue against such an association, 28 the study by Zhou et al indicates that in some experimental systems JNK suppression may additionally induce resistance through favoring a P-gP( þ ) phenotype.…”

Section: Discussionmentioning

confidence: 86%

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

et al. 2008

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Methylation-Controlled J Protein Promotes c-Jun Degradation To Prevent ABCB1 Transporter Expression

Abstract: Methylation-controlled J protein (MCJ) is a newly identified member of the

Cited by 52 publications

References 54 publications

Rewired Metabolism in Drug-resistant Leukemia Cells

Rewired Metabolism in Drug-resistant Leukemia Cells

Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

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