Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.

doi:10.1016/J.CELL.2005.07.002

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Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.

Journal Article•DOI•

Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.

Sophie Pattingre¹, Sophie Pattingre², Amina T. Tassa², Xueping Qu², Xueping Qu¹, Rita Garuti², Xiao Huan Liang¹, Noboru Mizushima³, Milton Packer², Michael D. Schneider⁴, Beth Levine¹, Beth Levine² - Show less +8 more•Institutions (4)

Columbia University¹, University of Texas Southwestern Medical Center², Institute of Medical Science³, Baylor College of Medicine⁴

23 Sep 2005-Cell (Cell Press)-Vol. 122, Iss: 6, pp 927-939

TL;DR: Bcl-2 not only functions as an antiapoptotic protein, but also as an antiautophagy protein via its inhibitory interaction with Beclin 1, which may help maintain autophagy at levels that are compatible with cell survival, rather than cell death.

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About: This article is published in Cell.The article was published on 2005-09-23 and is currently open access. It has received 3384 citations till now. The article focuses on the topics: BECN1 & Autophagy.

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Journal Article•DOI•

Autophagy in the Pathogenesis of Disease

[...]

Beth Levine¹, Guido Kroemer², Guido Kroemer³, Guido Kroemer⁴•Institutions (4)

University of Texas Southwestern Medical Center¹, University of Paris-Sud², French Institute of Health and Medical Research³, Institut Gustave Roussy⁴

11 Jan 2008-Cell

TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.

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6,301 citations

Cites background from "Bcl-2 antiapoptotic proteins inhibi..."

...In addition, ER-localized Bcl-2 and Bcl-XL inhibit autophagy by binding to the Beclin 1 autophagy protein (Pattingre et al., 2005; Maiuri et al., 2007b)....
[...]

Journal Article•DOI•

Autophagy fights disease through cellular self-digestion

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Noboru Mizushima¹, Beth Levine², Ana Maria Cuervo³, Daniel J. Klionsky⁴•Institutions (4)

Tokyo Medical and Dental University¹, University of Texas at Dallas², Yeshiva University³, University of Michigan⁴

28 Feb 2008-Nature

TL;DR: Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health, and to play a role in cell death.

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Abstract: Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

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5,831 citations

Journal Article•DOI•

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

[...]

Daniel J. Klionsky¹, Kotb Abdelmohsen², Akihisa Abe³, Joynal Abedin⁴ +2519 more•Institutions (695)

21 Jan 2016-Autophagy

TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.

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Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

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5,187 citations

Journal Article•DOI•

Guidelines for the use and interpretation of assays for monitoring autophagy

[...]

Daniel J. Klionsky¹, Fábio Camargo Abdalla², Hagai Abeliovich³, Robert T. Abraham⁴ +1284 more•Institutions (463)

01 Apr 2012-Autophagy

TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.

...read moreread less

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

...read moreread less

4,316 citations

Cites background from "Bcl-2 antiapoptotic proteins inhibi..."

...BECN1 is inhibited by its binding to the anti-apoptotic protein BCL2....
[...]
...Although a population of BECN1 may localize in proximity to the trans-Golgi network,(433) it is also present at the ER and mitochondria.(425) In keeping with these observations, in cerebellar organotypic cultures BECN1 co-immunoprecipitates with BCL2 that is primarily localized at the mitochondria and ER, and in a mouse model of neurodegeneration autophagic vacuoles in Purkinje neurons contain partially digested organelles that are immunoreactive for BCL2....
[...]
...Do not distribute. that is primarily localized at the mitochondria and ER, and in a mouse model of neurodegeneration autophagic vacuoles in Purkinje neurons contain partially digested organelles that are immunoreactive for BCL2....
[...]
...BECN1 is inhibited by its binding to the anti-apoptotic protein BCL2.(425) Autophagy is induced by the release of BECN1 from BCL2 by pro-apoptotic BH3 proteins, phosphorylation of BECN1 by DAPK (at Thr119, located in the BH3 domain),(426) or phosphorylation of BCL2 by JNK1 (at Thr69, Ser70 and Ser87)....
[...]

Journal Article•DOI•

Autophagy: process and function

[...]

Noboru Mizushima¹•Institutions (1)

Tokyo Medical and Dental University¹

15 Nov 2007-Genes & Development

TL;DR: In this review, the process of autophagy is summarized, and the role of autophileagy is discussed in a process-based manner.

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Abstract: Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Despite its simplicity, recent progress has demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles, which are sometimes complex. Autophagy consists of several sequential steps--sequestration, transport to lysosomes, degradation, and utilization of degradation products--and each step may exert different function. In this review, the process of autophagy is summarized, and the role of autophagy is discussed in a process-based manner.

...read moreread less

3,527 citations

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References

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Journal Article•DOI•

Cell Death: Critical Control Points

[...]

Nika N. Danial¹, Stanley J. Korsmeyer¹•Institutions (1)

Howard Hughes Medical Institute¹

23 Jan 2004-Cell

TL;DR: The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics.

...read moreread less

4,741 citations

"Bcl-2 antiapoptotic proteins inhibi..." refers background in this paper

...…pathway, although it has been recognized that Bcl-2 family members are multifunctional proteins that can influence other cellular processes, including cell cycle progression, calcineurin signaling, glucose homeostasis, and transcriptional repression by p53 (Danial and Korsmeyer, 2004; Reed, 1998)....
[...]
...…originally discovered in the context of its translocation next to the immunoglobulin gene promoter at the chromosomal breakpoint of t(14;18) bearing human follicular lymphoma, and transgenic mice harboring a Bcl-2 immunoglobulin minigene develop follicular hyperplasia (Danial and Korsmeyer, 2004)....
[...]

Journal Article•DOI•

Development by Self-Digestion: Molecular Mechanisms and Biological Functions of Autophagy

[...]

Beth Levine¹, Daniel J. Klionsky²•Institutions (2)

Columbia University¹, University of Michigan²

01 Apr 2004-Developmental Cell

TL;DR: This review summarizes the current knowledge about the molecular machinery of autophagy and the role of the autophagic machinery in eukaryotic development and identifies a set of evolutionarily conserved genes that are essential forAutophagy.

...read moreread less

3,721 citations

"Bcl-2 antiapoptotic proteins inhibi..." refers background in this paper

...Furthermore, the protective actions of autophagy against infection with intracellular pathogens, protein aggregation diseases, and aging in metazoan organisms (Levine and Yuan, 2005) are likely to represent a prosurvival function at the cellular level....
[...]
...Moreover, complex interrelationships are likely to exist between autophagy and the apoptotic cell death pathway (Levine and Yuan, 2005)....
[...]
...Previous studies have indirectly implicated a role for Bcl-2 in the negative regulation of autophagy (Levine and Yuan, 2005)....
[...]
...…for diverse aspects of biology, since autophagy genes play a role in promoting survival during stress conditions, in differentiation and development, in lifespan extension, in tumor suppression, and in cell death in apoptosis-deficient cells (Levine and Klionsky, 2004; Levine and Yuan, 2005)....
[...]
...Sophie Pattingre,1,2 Amina Tassa,2 Xueping Qu,1,2 Rita Garuti,3 Xiao Huan Liang,1,8 Noboru Mizushima,4,5 Milton Packer,6 Michael D. Schneider,7 and Beth Levine1,2,* 1Department of Medicine Columbia University College of Physicians & Surgeons New York, New York 10032 2Department of Internal Medicine…...
[...]

Journal Article•DOI•

Induction of autophagy and inhibition of tumorigenesis by beclin 1.

[...]

Xiao Huan Liang¹, Saadiya Jackson¹, Matthew N.J. Seaman, Kristy A. Brown¹, Bettina Kempkes, Hanina Hibshoosh¹, Beth Levine - Show less +3 more•Institutions (1)

Columbia University¹

09 Dec 1999-Nature

TL;DR: It is shown that beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma, suggesting that decreased expression of Autophagy proteins may contribute to the development or progression of breast and other human malignancies.

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Abstract: The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway, is important in normal growth control and may be defective in tumour cells. However, little is known about the genetic mediators of autophagy in mammalian cells or their role in tumour development. The mammalian gene encoding Beclin 1, a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30, and is mono-allelically deleted in 40-75% of sporadic human breast cancers and ovarian cancers. Here we show, using gene-transfer techniques, that beclin 1 promotes autophagy in autophagy-defective yeast with a targeted disruption of agp6/vps30, and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of beclin 1 in MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogenous Beclin 1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissue, but is expressed ubiquitously at high levels in normal breast epithelia. Thus, beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of breast and other human malignancies.

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3,178 citations

Journal Article•DOI•

The role of autophagy during the early neonatal starvation period

[...]

Akiko Kuma¹, Masahiko Hatano², Makoto Matsui³, Makoto Matsui⁴, Akitsugu Yamamoto⁵, Haruaki Nakaya², Tamotsu Yoshimori⁶, Yoshinori Ohsumi³, Takeshi Tokuhisa², Noboru Mizushima³, Noboru Mizushima¹, Noboru Mizushima⁴ - Show less +8 more•Institutions (6)

National Presto Industries¹, Chiba University², Graduate University for Advanced Studies³, Institute of Medical Science⁴, Nagahama Institute of Bio-Science and Technology⁵, National Institute of Genetics⁶

23 Dec 2004-Nature

TL;DR: The results suggest that the production of amino acids by autophagic degradation of ‘self’ proteins, which allows for the maintenance of energy homeostasis, is important for survival during neonatal starvation.

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Abstract: At birth the trans-placental nutrient supply is suddenly interrupted, and neonates face severe starvation until supply can be restored through milk nutrients. Here, we show that neonates adapt to this adverse circumstance by inducing autophagy. Autophagy is the primary means for the degradation of cytoplasmic constituents within lysosomes. The level of autophagy in mice remains low during embryogenesis; however, autophagy is immediately upregulated in various tissues after birth and is maintained at high levels for 3-12 h before returning to basal levels within 1-2 days. Mice deficient for Atg5, which is essential for autophagosome formation, appear almost normal at birth but die within 1 day of delivery. The survival time of starved Atg5-deficient neonates (approximately 12 h) is much shorter than that of wild-type mice (approximately 21 h) but can be prolonged by forced milk feeding. Atg5-deficient neonates exhibit reduced amino acid concentrations in plasma and tissues, and display signs of energy depletion. These results suggest that the production of amino acids by autophagic degradation of 'self' proteins, which allows for the maintenance of energy homeostasis, is important for survival during neonatal starvation.

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2,775 citations

"Bcl-2 antiapoptotic proteins inhibi..." refers background in this paper

...Beclin 1 is part of a Class III PI3K complex that participates in autophagosome formation, mediating the localization of other autophagy proteins to the preautophagosomal membrane ( Kihara et al., 2001 )....
[...]
...It is possible that Bcl-2 results in a redistribution of Beclin 1 away from the TGN (where it is active in autophagy induction; Kihara et al., 2001 ) to the ER; however, we did not observe any differences in the amount of Beclin 1 localized to the ER in cells that express low or high levels of Bcl-2 (data not shown)....
[...]
...In HT-29 cells, the inhibitory effects of Bcl-2 are associated with disruption of the Beclin 1/hVps34 complexes, which are thought to be essential for early stages of autophagosomal formation ( Kihara et al., 2001 )....
[...]
...…neonatal lethality in mice following interruption of the placental food supply, accelerated death of growth factor-deprived, apoptosis-resistant fibroblasts, and apoptosis of starved HeLa cells (Boya et al., 2005; Kuma et al., 2004; Levine and Klionsky, 2004; Liu et al., 2005; Lum et al., 2005)....
[...]
...While overexpressed Beclin 1 colocalized with Bcl-2 in the mitochondria and ER in COS7 cells (Liang et al., 1998), endogenous Beclin 1 has been reported to localize predominantly to the TGN ( Kihara et al., 2001 )....
[...]

Journal Article•DOI•

In Vivo Analysis of Autophagy in Response to Nutrient Starvation Using Transgenic Mice Expressing a Fluorescent Autophagosome Marker

[...]

Noboru Mizushima¹, Akitsugu Yamamoto², Makoto Matsui³, Makoto Matsui¹, Tamotsu Yoshimori⁴, Yoshinori Ohsumi¹, Yoshinori Ohsumi³ - Show less +3 more•Institutions (4)

National Institute for Basic Biology, Japan¹, Nagahama Institute of Bio-Science and Technology², Graduate University for Advanced Studies³, National Institute of Genetics⁴

29 Dec 2003-Molecular Biology of the Cell

TL;DR: The results suggest that the regulation of autophagy is organ dependent and the role of Aut7/Apg8 is not restricted to the starvation response, and this transgenic mouse model is a useful tool to study mammalian autophagic regulation.

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Abstract: Macroautophagy mediates the bulk degradation of cytoplasmic components. It accounts for the degradation of most long-lived proteins: cytoplasmic constituents, including organelles, are sequestered into autophagosomes, which subsequently fuse with lysosomes, where degradation occurs. Although the possible involvement of autophagy in homeostasis, development, cell death, and pathogenesis has been repeatedly pointed out, systematic in vivo analysis has not been performed in mammals, mainly because of a limitation of monitoring methods. To understand where and when autophagy occurs in vivo, we have generated transgenic mice systemically expressing GFP fused to LC3, which is a mammalian homologue of yeast Atg8 (Aut7/Apg8) and serves as a marker protein for autophagosomes. Fluorescence microscopic analyses revealed that autophagy is differently induced by nutrient starvation in most tissues. In some tissues, autophagy even occurs actively without starvation treatments. Our results suggest that the regulation of autophagy is organ dependent and the role of autophagy is not restricted to the starvation response. This transgenic mouse model is a useful tool to study mammalian autophagy.

...read moreread less

2,238 citations

"Bcl-2 antiapoptotic proteins inhibi..." refers methods in this paper

...pEGFP/LC3 and pEGFP/2xFYVE plasmids were kindly provided by Noboru Mizushima and Lewis Cantley, respectively (Mizushima et al., 2004; Viera et al., 2001)....
[...]