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Article ; Online: Involvement of CASP9 (caspase 9) in IGF2R/CI-MPR endosomal transport.

Han, Jie / Goldstein, Leslie A / Hou, Wen / Watkins, Simon C / Rabinowich, Hannah

2020 Volume 17, Issue 6, Page(s) 1393–1409

Abstract: Recently, we reported that increased expression of CASP9 pro-domain, at the endosomal membrane in response to HSP90 inhibition, mediates a cell-protective effect that does not involve CASP9 apoptotic activity. We report here that a non-apoptotic activity ...

Abstract	Recently, we reported that increased expression of CASP9 pro-domain, at the endosomal membrane in response to HSP90 inhibition, mediates a cell-protective effect that does not involve CASP9 apoptotic activity. We report here that a non-apoptotic activity of endosomal membrane CASP9 facilitates the retrograde transport of IGF2R/CI-MPR from the endosomes to the trans-Golgi network, indicating the involvement of CASP9 in endosomal sorting and lysosomal biogenesis. CASP9-deficient cells demonstrate the missorting of CTSD (cathepsin D) and other acid hydrolases, accumulation of late endosomes, and reduced degradation of bafilomycin A
MeSH term(s)	Autophagy/genetics ; Autophagy/physiology ; Caspase 9/genetics ; Caspase 9/metabolism ; Endosomes/metabolism ; HeLa Cells ; Humans ; Microtubule-Associated Proteins/metabolism ; Protein Transport/physiology ; Receptor, IGF Type 2/genetics ; Receptor, IGF Type 2/metabolism ; Vesicular Transport Proteins/metabolism ; trans-Golgi Network/metabolism
Chemical Substances	IGF2R protein, human ; Microtubule-Associated Proteins ; Receptor, IGF Type 2 ; Vesicular Transport Proteins ; CASP9 protein, human (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-)
Language	English
Publishing date	2020-05-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2020.1761742
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Article ; Online: HSP90 inhibition targets autophagy and induces a CASP9-dependent resistance mechanism in NSCLC.

Han, Jie / Goldstein, Leslie A / Hou, Wen / Chatterjee, Suman / Burns, Timothy F / Rabinowich, Hannah

Autophagy

2018 Volume 14, Issue 6, Page(s) 958–971

Abstract: Macroautophagy/autophagy has emerged as a resistance mechanism to anticancer drug treatments that induce metabolic stress. Certain tumors, including a subset of KRAS-mutant NSCLCs have been shown to be addicted to autophagy, and potentially vulnerable to ...

Abstract	Macroautophagy/autophagy has emerged as a resistance mechanism to anticancer drug treatments that induce metabolic stress. Certain tumors, including a subset of KRAS-mutant NSCLCs have been shown to be addicted to autophagy, and potentially vulnerable to autophagy inhibition. Currently, autophagy inhibition is being tested in the clinic as a therapeutic component for tumors that utilize this degradation process as a drug resistance mechanism. The current study provides evidence that HSP90 (heat shock protein 90) inhibition diminishes the expression of ATG7, thereby impeding the cellular capability of mounting an effective autophagic response in NSCLC cells. Additionally, an elevation in the expression level of CASP9 (caspase 9) prodomain in KRAS-mutant NSCLC cells surviving HSP90 inhibition appears to serve as a cell survival mechanism. Initial characterization of this survival mechanism suggests that the altered expression of CASP9 is mainly ATG7 independent; it does not involve the apoptotic activity of CASP9; and it localizes to a late endosomal and pre-lysosomal phase of the degradation cascade. HSP90 inhibitors are identified here as a pharmacological approach for targeting autophagy via destabilization of ATG7, while an induced expression of CASP9, but not its apoptotic activity, is identified as a resistance mechanism to the cellular stress brought about by HSP90 inhibition.
MeSH term(s)	Autophagy/drug effects ; Autophagy-Related Protein 7/metabolism ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Caspase 9/chemistry ; Caspase 9/metabolism ; Cell Line, Tumor ; Cytoprotection/drug effects ; Down-Regulation/drug effects ; Drug Resistance, Neoplasm ; Enzyme Stability/drug effects ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mutation/genetics ; Protein Domains ; Triazoles/pharmacology ; Up-Regulation/drug effects ; Up-Regulation/genetics
Chemical Substances	HSP90 Heat-Shock Proteins ; STA 9090 ; Triazoles ; Caspase 9 (EC 3.4.22.-) ; Autophagy-Related Protein 7 (EC 6.2.1.45)
Language	English
Publishing date	2018-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2018.1434471
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Article ; Online: A Complex between Atg7 and Caspase-9: A NOVEL MECHANISM OF CROSS-REGULATION BETWEEN AUTOPHAGY AND APOPTOSIS.

Han, Jie / Hou, Wen / Goldstein, Leslie A / Stolz, Donna B / Watkins, Simon C / Rabinowich, Hannah

The Journal of biological chemistry

2013 Volume 289, Issue 10, Page(s) 6485–6497

Abstract: Several cross-talk mechanisms between autophagy and apoptosis have been identified, in which certain co-regulators are shared, allowing the same protein to participate in these opposing processes. Our studies suggest that caspase-9 is a novel co- ... ...

Abstract	Several cross-talk mechanisms between autophagy and apoptosis have been identified, in which certain co-regulators are shared, allowing the same protein to participate in these opposing processes. Our studies suggest that caspase-9 is a novel co-regulator of apoptosis and autophagy and that its caspase catalytic activity is dispensable for its autophagic role. We provide evidence that caspase-9 facilitates the early events leading to autophagosome formation; that it forms a complex with Atg7; that Atg7 is not a direct substrate for caspase-9 proteolytic activity; and that, depending on the cellular context, Atg7 represses the apoptotic capability of caspase-9, whereas the latter enhances the Atg7-mediated formation of light chain 3-II. The repression of caspase-9 apoptotic activity is mediated by its direct interaction with Atg7, and it is not related to the autophagic function of Atg7. We propose that the Atg7·caspase-9 complex performs a dual function of linking caspase-9 to the autophagic process while keeping in check its apoptotic activity.
MeSH term(s)	Animals ; Apoptosis ; Autophagy ; Autophagy-Related Protein 7 ; Caspase 9/genetics ; Caspase 9/metabolism ; Cell Line, Tumor ; Humans ; Mice ; Microtubule-Associated Proteins/metabolism ; Multienzyme Complexes/genetics ; Multienzyme Complexes/metabolism ; RNA, Small Interfering/genetics ; Ubiquitin-Activating Enzymes/genetics ; Ubiquitin-Activating Enzymes/metabolism
Chemical Substances	MAP1LC3A protein, human ; Microtubule-Associated Proteins ; Multienzyme Complexes ; RNA, Small Interfering ; CASP9 protein, human (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-) ; ATG7 protein, human (EC 6.2.1.45) ; Autophagy-Related Protein 7 (EC 6.2.1.45) ; Ubiquitin-Activating Enzymes (EC 6.2.1.45)
Language	English
Publishing date	2013-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.536854
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Article: 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 / Gastman, Brian R / Rabinowich, Hannah

Journal of biological chemistry. 2010 July 16, v. 285, no. 29

2010

Abstract: Multiple mechanisms have been proposed for the mitochondrial function of p53 that are either dependent on or independent of its transcriptional activity. However, none of these mechanisms involves Bim functioning downstream of p53 mitochondrial ... ...

Abstract	Multiple mechanisms have been proposed for the mitochondrial function of p53 that are either dependent on or independent of its transcriptional activity. However, none of these mechanisms involves Bim functioning downstream of p53 mitochondrial translocation. Utilizing a p53 nuclear localization signal mutant, whose nuclear import is completely abrogated, we demonstrate that its apoptotic activity at the outer mitochondrial membrane, which involves conformational changes in Bax and Bak, is mediated by Bim. We further demonstrate an inverse correlation between the binding levels of p53 and Bim to Mcl-1. Thus, enhanced binding of p53 to Mcl-1 involves the disruption of existing complexes between Mcl-1 and Bim. We propose that mitochondrial p53 functions as a Bim derepressor by releasing Bim from sequestrating complexes with Mcl-1, Bcl-2, and Bcl-XL, and allowing its engagement in Bak/Bax activation.
Language	English
Dates of publication	2010-0716
Size	p. 22473-22483.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: Functional linkage between NOXA and Bim in mitochondrial apoptotic events.

Han, Jie / Goldstein, Leslie A / Hou, Wen / Rabinowich, Hannah

The Journal of biological chemistry

2007 Volume 282, Issue 22, Page(s) 16223–16231

Abstract: NOXA is a BH3-only protein whose expression is induced by certain p53-depenent or independent apoptotic stimuli. Both NOXA and Bim are avid binders of Mcl-1, but a functional linkage between these BH3-only proteins has not yet been reported. In this ... ...

Abstract	NOXA is a BH3-only protein whose expression is induced by certain p53-depenent or independent apoptotic stimuli. Both NOXA and Bim are avid binders of Mcl-1, but a functional linkage between these BH3-only proteins has not yet been reported. In this study, we demonstrate that Mcl-1 binding of endogenously induced NOXA interferes with the ability of Mcl-1 to efficiently sequester endogenous Bim, as Bim is displaced from its complex with Mcl-1. Induced NOXA significantly enhances the UV sensitivity of cells, and the ensuing mitochondrial depolarization is entirely abrogated by Bim knockdown. These results demonstrate a Mcl-1-mediated cross-talk between endogenous NOXA and Bim that occurs upstream of the Bak/Bax-dependent execution of UV-induced mitochondrial depolarization. The current findings demonstrate that the mitochondrial response to an induced expression of NOXA is executed by endogenous Bim and suggest a plausible mechanism for the observed NOXA-Bim linkage.
MeSH term(s)	Apoptosis/genetics ; Apoptosis/radiation effects ; Apoptosis Regulatory Proteins/biosynthesis ; Apoptosis Regulatory Proteins/genetics ; Bcl-2-Like Protein 11 ; HeLa Cells ; Humans ; Jurkat Cells ; Membrane Proteins/biosynthesis ; Membrane Proteins/genetics ; Mitochondria/genetics ; Mitochondria/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Protein Binding/genetics ; Protein Binding/radiation effects ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Ultraviolet Rays ; bcl-2 Homologous Antagonist-Killer Protein/genetics ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; BAK1 protein, human ; BAX protein, human ; BCL2L11 protein, human ; Bcl-2-Like Protein 11 ; Membrane Proteins ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins ; PMAIP1 protein, human ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Tumor Suppressor Protein p53 ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein
Language	English
Publishing date	2007-03-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M611186200
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Article ; Online: Reciprocal granzyme/perforin-mediated death of human regulatory and responder T cells is regulated by interleukin-2 (IL-2).

Czystowska, Malgorzata / Strauss, Laura / Bergmann, Christoph / Szajnik, Marta / Rabinowich, Hannah / Whiteside, Theresa L

Journal of molecular medicine (Berlin, Germany)

2010 Volume 88, Issue 6, Page(s) 577–588

Abstract: Human CD4(+)CD25(high)FOXP3(+) T regulatory cells (Treg) can suppress responder T cell (RC) functions by various mechanisms. In co-cultures of Treg and autologous activated RC, both cell subsets up-regulate the expression of granzymes and perforin, which ...

Abstract	Human CD4(+)CD25(high)FOXP3(+) T regulatory cells (Treg) can suppress responder T cell (RC) functions by various mechanisms. In co-cultures of Treg and autologous activated RC, both cell subsets up-regulate the expression of granzymes and perforin, which might contribute to Treg-mediated suppression. Here, we investigate the sensitivity and resistance of Treg and RC to granzyme/perforin-mediated death. CD4(+)CD25(neg) RC were single cell-sorted from the peripheral blood of 25 cancer patients and 15 normal controls. These RC were carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled and co-cultured with autologous CD4(+)CD25(high)FOXP3(+) Treg +/- 150 or +/-1,000 IU/mL of interleukin-2 (IL-2) to evaluate suppression of RC proliferation. In addition, survival of the cells co-cultured for 24 h and 5 days was measured using a flow-based cytotoxicity assay. Freshly isolated Treg and RC expressed granzyme A (GrA), granzyme B (GrB), and perforin. Percentages of positive cells were higher in cancer patients than controls (p < 0.01) and increased upon OKT3 and IL-2 stimulation. Treg, co-cultured with RC at 150 IU/mL of IL-2, no longer expressed cytotoxins and became susceptible to RC-mediated, granzyme/perforin-dependent death. However, in co-cultures with 1,000 IU/mL of IL-2, Treg became resistant to apoptosis and induced GrB-dependent, perforin-independent death of RC. When the GrB inhibitor I or GrB-specific and GrA-specific small inhibitory ribonucleic acids were used to block the granzyme pathway in Treg, RC death, and Treg-mediated suppression of RC, proliferation were significantly inhibited. Human CD4(+)CD25(high) Treg and CD4(+)CD25(neg) RC reciprocally regulate death/growth arrest by differentially utilizing the granzyme-perforin pathway depending on IL-2 concentrations.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Animals ; CD4 Antigens/immunology ; Cells, Cultured ; Coculture Techniques ; Female ; Granzymes/genetics ; Granzymes/metabolism ; Humans ; Interleukin-2/immunology ; Interleukin-2 Receptor alpha Subunit/immunology ; Male ; Middle Aged ; Neoplasms/immunology ; Perforin ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; T-Lymphocyte Subsets/cytology ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Regulatory/cytology ; T-Lymphocytes, Regulatory/immunology ; Young Adult
Chemical Substances	CD4 Antigens ; Interleukin-2 ; Interleukin-2 Receptor alpha Subunit ; RNA, Small Interfering ; Perforin (126465-35-8) ; Granzymes (EC 3.4.21.-)
Language	English
Publishing date	2010-06
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-010-0602-9
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Article ; Online: 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 / Gastman, Brian R / Rabinowich, Hannah

The Journal of biological chemistry

2010 Volume 285, Issue 29, Page(s) 22473–22483

Abstract	Multiple mechanisms have been proposed for the mitochondrial function of p53 that are either dependent on or independent of its transcriptional activity. However, none of these mechanisms involves Bim functioning downstream of p53 mitochondrial translocation. Utilizing a p53 nuclear localization signal mutant, whose nuclear import is completely abrogated, we demonstrate that its apoptotic activity at the outer mitochondrial membrane, which involves conformational changes in Bax and Bak, is mediated by Bim. We further demonstrate an inverse correlation between the binding levels of p53 and Bim to Mcl-1. Thus, enhanced binding of p53 to Mcl-1 involves the disruption of existing complexes between Mcl-1 and Bim. We propose that mitochondrial p53 functions as a Bim derepressor by releasing Bim from sequestrating complexes with Mcl-1, Bcl-2, and Bcl-XL, and allowing its engagement in Bak/Bax activation.
MeSH term(s)	Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Bcl-2-Like Protein 11 ; Binding, Competitive ; Cell Line, Tumor ; Humans ; Immunoprecipitation ; Membrane Potential, Mitochondrial ; Membrane Proteins/metabolism ; Mitochondria/metabolism ; Models, Biological ; Mutation/genetics ; Myeloid Cell Leukemia Sequence 1 Protein ; Nuclear Localization Signals/metabolism ; Protein Binding ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Stress, Physiological ; Subcellular Fractions/metabolism ; Tumor Suppressor Protein p53/metabolism ; bcl-X Protein/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; BBC3 protein, human ; BCL2L11 protein, human ; Bcl-2-Like Protein 11 ; Membrane Proteins ; Myeloid Cell Leukemia Sequence 1 Protein ; Nuclear Localization Signals ; PMAIP1 protein, human ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Tumor Suppressor Protein p53 ; bcl-X Protein
Language	English
Publishing date	2010-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M109.081042
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Article ; Online: Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis.

Hou, Wen / Han, Jie / Lu, Caisheng / Goldstein, Leslie A / Rabinowich, Hannah

Autophagy

2010 Volume 6, Issue 7, Page(s) 891–900

Abstract: Apoptotic defects endow tumor cells with survival advantages. Such defects allow the cellular stress response to take the path of cytoprotective autophagy, which either precedes or effectively blocks an apoptotic cascade. Inhibition of the cytoprotective ...

Abstract	Apoptotic defects endow tumor cells with survival advantages. Such defects allow the cellular stress response to take the path of cytoprotective autophagy, which either precedes or effectively blocks an apoptotic cascade. Inhibition of the cytoprotective autophagic response shifts the cells toward apoptosis, by interfering with an underlying molecular mechanism of cytoprotection. The current study has identified such a mechanism that is centered on the regulation of caspase-8 activity. The study took advantage of Bax(-/-) Hct116 cells that are TRAIL-resistant despite significant DISC processing of caspase-8, and of the availability of a caspase-8-specific antibody that exclusively detects the caspase-8 large subunit or its processed precursor. Utilizing these biological tools, we investigated the expression pattern and subcellular localization of active caspase-8 in TRAIL-mediated autophagy and in the autophagy-to-apoptosis shift upon autophagy inhibition. Our results suggest that the TRAIL-mediated autophagic response counter-balances the TRAIL-mediated apoptotic response by the continuous sequestration of the large caspase-8 subunit in autophagosomes and its subsequent elimination in lysosomes. The current findings are the first to provide evidence for regulation of caspase activity by autophagy and thus broaden the molecular basis for the observed polarization between autophagy and apoptosis.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/physiology ; Beclin-1 ; Caspase 8/metabolism ; Cell Line, Tumor ; Cisplatin/pharmacology ; Gene Knockdown Techniques ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Pepstatins/metabolism ; Protease Inhibitors/metabolism ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Antineoplastic Agents ; Apoptosis Regulatory Proteins ; BECN1 protein, human ; Beclin-1 ; MAP1LC3A protein, human ; Membrane Proteins ; Microtubule-Associated Proteins ; Pepstatins ; Protease Inhibitors ; TNF-Related Apoptosis-Inducing Ligand ; bcl-2-Associated X Protein ; Caspase 8 (EC 3.4.22.-) ; Cisplatin (Q20Q21Q62J) ; pepstatin (V6Y2T27Q1U)
Language	English
Publishing date	2010-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.6.7.13038
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Article ; Online: Deregulation of mitochondrial membrane potential by mitochondrial insertion of granzyme B and direct Hax-1 cleavage.

Han, Jie / Goldstein, Leslie A / Hou, Wen / Froelich, Christopher J / Watkins, Simon C / Rabinowich, Hannah

The Journal of biological chemistry

2010 Volume 285, Issue 29, Page(s) 22461–22472

Abstract: The cytoplasm and the nucleus have been identified as activity sites for granzyme B (GrB) following its delivery from cytotoxic lymphocyte granules into target cells. Here we report on the ability of exogenous GrB to insert into and function within a ... ...

Abstract	The cytoplasm and the nucleus have been identified as activity sites for granzyme B (GrB) following its delivery from cytotoxic lymphocyte granules into target cells. Here we report on the ability of exogenous GrB to insert into and function within a proteinase K-resistant mitochondrial compartment. We identified Hax-1 (HS-1-associated protein X-1), a mitochondrial protein involved in the maintenance of mitochondrial membrane potential, as a GrB substrate within the mitochondrion. GrB cleaves Hax-1 into two major fragments: an N-terminal fragment that localizes to mitochondria and a C-terminal fragment that localizes to the cytosol after being released from GrB-treated mitochondria. The N-terminal Hax-1 fragment major cellular impact is on the regulation of mitochondrial polarization. Overexpression of wild-type Hax-1 or its uncleavable mutant form protects the mitochondria against GrB or valinomycin-mediated depolarization. The N-terminal Hax-1 fragment functions as a dominant negative form of Hax-1, mediating mitochondrial depolarization in a cyclophilin D-dependent manner. Thus, induced expression of the N-terminal Hax-1 fragment results in mitochondrial depolarization and subsequent lysosomal degradation of such altered mitochondria. This study is the first to demonstrate GrB activity within the mitochondrion and to identify Hax-1 cleavage as a novel mechanism for GrB-mediated mitochondrial depolarization.
MeSH term(s)	Adaptor Proteins, Signal Transducing/chemistry ; Adaptor Proteins, Signal Transducing/metabolism ; Cell Compartmentation/drug effects ; Cell Line, Tumor ; Peptidyl-Prolyl Isomerase F ; Cyclophilins/pharmacology ; Gene Knockdown Techniques ; Granzymes/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Mitochondria/enzymology ; Mitochondrial Proteins/metabolism ; Peptide Fragments/metabolism ; Protein Transport/drug effects ; Subcellular Fractions/drug effects ; Subcellular Fractions/metabolism ; Tetracycline/pharmacology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Peptidyl-Prolyl Isomerase F ; HAX1 protein, human ; Mitochondrial Proteins ; Peptide Fragments ; GZMB protein, human (EC 3.4.21.-) ; Granzymes (EC 3.4.21.-) ; Cyclophilins (EC 5.2.1.-) ; Tetracycline (F8VB5M810T)
Language	English
Publishing date	2010-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M109.086587
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Article ; Online: Interaction between Her2 and Beclin-1 proteins underlies a new mechanism of reciprocal regulation.

Han, Jie / Hou, Wen / Lu, Caisheng / Goldstein, Leslie A / Stolz, Donna B / Watkins, Simon C / Rabinowich, Hannah

The Journal of biological chemistry

2013 Volume 288, Issue 28, Page(s) 20315–20325

Abstract: Beclin-1 is a key regulator of autophagy that functions in the context of two phase-specific complexes in the initiation and maturation of autophagosomes. Its known interacting proteins include autophagy effectors, Bcl-2 family members, and organelle ... ...

Abstract	Beclin-1 is a key regulator of autophagy that functions in the context of two phase-specific complexes in the initiation and maturation of autophagosomes. Its known interacting proteins include autophagy effectors, Bcl-2 family members, and organelle membrane anchor proteins. Here we report a newly identified interaction between Beclin-1 and the protein tyrosine kinase receptor Her2. We demonstrate that in Her2-expressing breast carcinoma cells that do not succumb to lapatinib, this Her1/2 inhibitor disrupts the cell surface interaction between Her2 and Beclin-1. The data suggest that the ensuing autophagic response is correlatively associated with the release of Beclin-1 from its complex with Her2 and with the subsequent increase in cytosolic Beclin-1. Upon its interaction with Her2, Beclin-1 up-regulates the phosphorylation levels of Her2 and Akt. The Beclin-1 evolutionarily conserved domain is required both for the interaction of Beclin-1 with Her2 and for the increased Her2 and Akt phosphorylation. These findings shed new light on mechanisms involved in lapatinib-mediated autophagy in Her2-expressing breast carcinoma cell lines and in Beclin-1 signaling in these cells.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Apoptosis/genetics ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/drug effects ; Autophagy/genetics ; Autophagy/physiology ; Beclin-1 ; Cell Line, Tumor ; Humans ; Jurkat Cells ; Lapatinib ; MCF-7 Cells ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Microscopy, Electron, Transmission ; Phagosomes/drug effects ; Phagosomes/metabolism ; Phagosomes/ultrastructure ; Phosphorylation/drug effects ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Quinazolines/pharmacology ; RNA Interference ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism
Chemical Substances	Antineoplastic Agents ; Apoptosis Regulatory Proteins ; BECN1 protein, human ; Beclin-1 ; Membrane Proteins ; Quinazolines ; Lapatinib (0VUA21238F) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2013-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.461350
Database	MEDical Literature Analysis and Retrieval System OnLINE

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