The flexible loop of Bcl‐2 is required for molecular interaction with immunosuppressant FK‐506 binding protein 38 (FKBP38)

Kang, CongBao; Tai, Jeff; Chia, Joel; Yoon, Ho Sup

doi:10.1016/j.febslet.2005.01.053

Cited by 47 publications

(61 citation statements)

References 19 publications

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“…In contrast, Shirane and Nakayama (2003) reported that the mitochondrial FK506-binding protein 38 (FKBP38) interacts with Bcl-2 and plays an important role in targeting Bcl-2 to the mitochondrial membrane. An FKBP38 interacting domain was recently mapped to the unstructured loop of Bcl-2 (Kang et al, 2005). In this study, we demonstrate that mitochondrial targeting of Mcl-1 is facilitated by Tom70 via the internal EELD motif, which is apparently absent in the Bcl-2 molecule.…”

Section: Discussionmentioning

confidence: 71%

“…It was further proposed that lack of specific mitochondrial targeting ability of the C-terminal hydrophobic tail of both Mcl-1 and Bcl-2 is mainly due to lack of sufficient basicity in this region of protein sequences (Kaufmann et al, 2003). Alternatively, FKBP38 was shown to facilitate the mitochondrial import of Bcl-2 (Shirane and Nakayama, 2003) and likely did so via binding to the N-terminal unstructured loop of Bcl-2 (Kang et al, 2005). These results suggest that, like with Mcl-1, mitochondrial targeting of Bcl-2 requires the collaboration of two protein domains, one in the N terminus and the other in the C-terminal end.…”

Section: Discussionmentioning

confidence: 99%

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An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway

Chou

Lee

Yang-Yen

2006

MBoC

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway

Chou

Lee

Yang-Yen

2006

MBoC

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“…FKBP38 is localized on the mitochondria and has been shown to anchor proteins like Bcl2 and Bcl-xl to this organelle (14). The FKBP38-mTOR interaction is not thought to be involved in the Rheb protein-mediated activation of mTOR (15,16). mTOR might possibly be localized to the mitochondria via an FKBP38-mediated anchoring mechanism.…”

Section: Resultsmentioning

confidence: 99%

Direct control of mitochondrial function by mTOR

Ramanathan

Schreiber

2009

Proc. Natl. Acad. Sci. U.S.A.

315

272

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mTOR is a central regulator of cellular growth and metabolism. Using metabolic profiling and numerous small-molecule probes, we investigated whether mTOR affects immediate control over cellular metabolism by posttranslational mechanisms. Inhibiting the FKBP12/rapamycin-sensitive subset of mTOR functions in leukemic cells enhanced aerobic glycolysis and decreased uncoupled mitochondrial respiration within 25 min. mTOR is in a complex with the mitochondrial outer-membrane protein Bcl-xl and VDAC1. Bcl-xl, but not VDAC1, is a kinase substrate for mTOR in vitro, and mTOR regulates the association of Bcl-xl with mTOR. Inhibition of mTOR not only enhances aerobic glycolysis, but also induces a state of increased dependence on aerobic glycolysis in leukemic cells, as shown by the synergy between the glycolytic inhibitor 2-deoxyglucose and rapamycin in decreasing cell viability.metabolomics ͉ mitochondria ͉ chemical biology m TOR functions as a multichannel processor in a cellular nutrient-sensing network by receiving multiple inputs derived from distinct environmental cues and directing different outputs to appropriate downstream effectors. Upstream regulators of mTOR are primarily mitogens, nutrients, and energy (1). mTOR exists in 2 separate protein complexes: the mitogen-, nutrient-, and rapamycin-sensitive mTOR complex 1 (mTORC1) and the mitogen-sensitive and nutrient-and rapamycin-insensitive mTORC2 (2). mTOR regulates key cellular processes, including mRNA translation, ribosome biogenesis, autophagy, and metabolism. The most extensively studied targets of mTOR are the translation regulators S6K1 and 4E-BP1 (3). Yeast cells treated with rapamycin mount an immediate (within 20 min) and widespread transcriptional response that results in metabolic reprogramming characteristic of the diauxic shift (4). Mammalian cells do not display an immediate and widespread transcriptional response to mTOR inhibition by rapamycin (5). Inhibition of mTORC1 using either rapamycin or RNA-mediated interference of proteins involved in the signaling network decreases mitochondrial respiration and levels of fully uncoupled respiration, independent of S6K1 and 4EBP1 (6). Recently, rapamycin was reported to decrease the transcription of genes involved in mitochondrial oxidative function by disrupting a complex involving TORC1, YY1, and PGC-1␣, thereby preventing the coactivation of YY1 by PGC-1␣ (7). The authors suggested this transcriptional mechanism as the means by which mTOR controls mitochondrial function; however, treatment with rapamycin does not result in decreased mitochondrial content (6) even after 8 h.Here we describe an immediate change in mitochondrial function following the inhibition of mTOR. Using global physiological profiling, we show that inhibition of mTOR has immediate effects on carbon and mitochondrial metabolism in a leukemic cell line. Rapamycin-treated leukemic cells display reduced mitochondrial function, resulting in energy production via enhanced aerobic glycolysis in preference over mitochondrial respiration....

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“…4,5,[29][30][31][32][33] Moreover, some bcl-2 protein interactors, such as the bcl-2 mitochondrial chaperone FKBP38, the orphan nuclear receptor Nur77 and the molecular chaperone HSP90, have been demonstrated to be involved in oxygen-dependent and -independent regulation of the HIF-1a protein. [33][34][35] Even if we recently demonstrated that bcl-2 protein under hypoxic conditions interacts with both HIF-1a and HSP90 proteins contributing to the enhancement of HIF-1a protein stability, 21 we cannot exclude that also other bcl-2 interactors can be involved in bcl-2-induced HIF-1a/VEGF regulation.…”

Section: Discussionmentioning

confidence: 99%

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Trisciuoglio¹,

Gabellini

Desideri³

et al. 2011

Cell Death Differ

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In addition to act as an antiapoptotic protein, B-cell lymphoma (bcl)-2 can also promote tumor angiogenesis. In this context, we have previously demonstrated that under hypoxia bcl-2 promotes hypoxia-inducible factor-1 (HIF-1)-mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. Here, we report on the role of the BH4 domain in bcl-2 functions, by showing that removal of or mutations at the BH4 domain abrogate the ability of bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells. We have also extended this observation to other human tumor histotypes, such as colon, ovarian and lung carcinomas. The involvement of BH4 on HIF-1a protein expression, stability, ubiquitination and HIF-1 transcriptional activity was also demonstrated in melanoma experimental model. Moreover, we validated the role of the BH4 domain of bcl-2 in the regulation of HIF-1/VEGF axis, demonstrating that BH4 peptide is sufficient to increase HIF-1a protein half-life impairing HIF-1a protein ubiquitination, and to enhance VEGF secretion in melanoma cells exposed to hypoxia. Finally, we found that the mechanism by which bcl-2 regulates HIF-1-mediated VEGF expression does not require BH1 and BH2 domains, and it is independent of antiapoptotic and prosurvival function of bcl-2.

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The flexible loop of Bcl‐2 is required for molecular interaction with immunosuppressant FK‐506 binding protein 38 (FKBP38)

Cited by 47 publications

References 19 publications

An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway

An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway

Direct control of mitochondrial function by mTOR

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

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