Regulation of Mitochondrial Apoptotic Events by p53-mediated Disruption of Complexes between Antiapoptotic Bcl-2 Members and Bim

Han, Jie; Goldstein, Leslie A.; Hou, Wen Chi; Gastman, Brian; Rabinowich, Hannah

doi:10.1074/jbc.m109.081042

Cited by 53 publications

(50 citation statements)

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“…Additional BH3-only proteins may be important in neomycin-induced toxicity, perhaps by preventing binding of Bcl2 to Bax, which could explain the lack of protection seen in the Bcl2 overexpression fish. This conjecture requires further exploration of BH3-only proteins such as Bim and Noxa that modulate Bcl2 interactions with other protein targets (Antonsson 2001;Han et al 2010).…”

Section: Bcl2 Proteins and Aminoglycoside Ototoxicitymentioning

confidence: 99%

“…Importantly, the slow form of Bax-independent death induced by DNA damage involved p53 activity (Besirli et al 2003). p53 can also interact directly with pro-survival and pro-cell death Blc2 family members to activate mitochondrial-associated cell death path-ways (Mihara et al 2003;Chipuk et al 2004;Moll et al 2005;Han et al 2010). Protein binding and colocalization experiments are necessary to further dissect the relative contributions of these proteins to aminoglycoside ototoxicity.…”

Section: Bcl2 Proteins and Aminoglycoside Ototoxicitymentioning

confidence: 99%

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Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

114

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Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.

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Section: Bcl2 Proteins and Aminoglycoside Ototoxicitymentioning

confidence: 99%

Section: Bcl2 Proteins and Aminoglycoside Ototoxicitymentioning

confidence: 99%

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

114

View full text Add to dashboard Cite

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“…Apoptotic Assays-Apoptotic assays included long-term clonogenicity, flow cytometry of propidium iodide and Annexin V, and immunoblotting for processed caspases or their substrates, as described previously (41,42,45,46). Caspase-9 activity was measured by the caspase-9 Glo Kit (Promega).…”

Section: Methodsmentioning

confidence: 99%

A Complex between Atg7 and Caspase-9

Han

Hou

Goldstein

et al. 2014

Journal of Biological Chemistry

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Background: Several cross-talk mechanisms between autophagy and apoptosis have been identified, where the same protein plays a central role in the opposing processes. Results: This study identified a novel cross-talk mechanism involving an Atg7⅐caspase-9 complex. Conclusion: Atg7 and caspase-9 mutually regulate each other's activity. Significance: The Atg7⅐caspase-9 complex may determine the balance between autophagy and apoptosis in response to stress.

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“…3B) by flow cytometry. The JC-1 dye allows for rapid monitoring of mitochondrial polarization through potential-dependent accumulation in mitochondria, indicated by a fluorescence emission shift from green (∼529 nm) to red (∼590 nm) (27). Consequently, mitochondrial depolarization is indicated by a decrease in red/green fluorescence intensity ratio.…”

Section: Matrix Screening Highlights Ruxolitinib Drug Combinations Thatmentioning

confidence: 99%

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Zhang

Griner

Wang

et al. 2015

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

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Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokinedependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.adult T-cell leukemia | Janus kinase | ruxolitinib | navitoclax T -cell leukemia/lymphoma represents ∼10% of lymphoid malignancies. Genetic alterations affecting members of the Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) were discovered in a variety of T-cell malignancies (1, 2). Furthermore, increases in the common γc cytokine concentrations that signal through the JAK1/3, STAT3/5 pathway have been demonstrated in angioimmunoblastic T-cell lymphoma, gamma delta T-cell lymphoma, and adult T-cell leukemia (ATL), thereby identifying effective therapeutic targets.ATL is an aggressive T-cell malignancy characterized by the clonal expansion of CD4 + CD25 + T lymphocytes that develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1 (HTLV-1) (3-5). Clinically, ATL is subclassified into four subtypes: smoldering, chronic, lymphomatous, and acute (4, 5). Presently, there is no curative therapy for ATL (4, 5). In search of effective therapies, we examined key signaling pathways that confer a proliferation and viability advantage to ATL cells. It was noted that the HTLV-1-encoded Tax (transactivator from the X-gene region) is associated with increased Bcl-xL (B-cell lymphoma-extra large) expression in ATL cells (6). Furthermore, we reported two autocrine loops (IL-2/IL-2Rα, IL-15/IL-15Rα) and one paracrine loop that in...

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Regulation of Mitochondrial Apoptotic Events by p53-mediated Disruption of Complexes between Antiapoptotic Bcl-2 Members and Bim

Cited by 53 publications

References 50 publications

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

A Complex between Atg7 and Caspase-9

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

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