apoptosi autofagia 15 -...
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![Page 1: Apoptosi autofagia 15 - Unifem.docente.unife.it/francesco.bernardi/materiale-didattico-macromole… · Apoptosi autofagia 15 Author: Aula B3 Created Date: 12/15/2015 10:01:44 AM Keywords](https://reader034.vdocuments.site/reader034/viewer/2022051907/5ffa99d29b432f68d121d124/html5/thumbnails/1.jpg)
11/12/2015 Ionut Atanasoai SBE 2015/2016
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autophagy
Beclin 1, complex with PI3K Vps34 and nucleation of the autophagosome membrane
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• Attivatori
• Anti-apoptotici
• Pro-apoptotici
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Globular structure with a central BH3-binding
hydrophobic groove
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• Amphipathic helix
• Activators conformational disorder(and the Bid exception)
• Hydrophobic residues(h0→h4) and salt bridge
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Second activation site for BaxAlpha 9 extrusion trigger
?
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It is widely accepted that Bcl-2 family members not only inhibit
apoptosis but also negatively regulate autophagy by binding to
Beclin 1
Lisa M. Lindqvist et al.,2014 PNAS
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Lisa M. Lindqvist et al.,2014 PNAS
Bax-/-Bak-/-Mcl-1-/-
Bax-/-Bak-/-Mcl-1-/- + VP-16
Mcl-1-/-
VP-16 chemotherapeutic agent etoposide,
inducer of autophagy
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We show that in the absence of Bax and Bak,
antagonizing or altering the levels of Bcl-2 has no
detectable impact on autophagy
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Beclin 1, formation of a complex with the mammalian PI3K Vps34
and nucleation of the autophagosome membrane
When nutrients are abundant, Bcl-2 and the related proteins Bcl-xL and Mcl-1 bind to the
Beclin 1’s BH3 domain and thereby inhibit induction of autophagy
When nutrients are scarce, Bcl-2 is phosphorylated by JNK1, which prevents its binding to
Beclin 1 and allows it to initiate formation of autophagosomes
BH3 mimetic ABT-737
VP-16 chemotherapeutic agent etoposide, inducer of autophagy, including the () or
nutrient starvation by culturing in HBSS, potent inducer of apoptosis
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When nutrients are abundant, Bcl-2 and the
related proteins Bcl-xL and Mcl-1 bind to the
Beclin 1’s BH3 domain and thereby inhibit
induction of autophagy
When nutrients are scarce (HBSS) , Bcl-2 is
phosphorylated which prevents its binding to
Beclin 1 and allows it to initiate formation of
autophagosomes
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� None of the prosurvival Bcl-2 family members bind to Beclin-1 under physiological circumstances or
they do not significantly inhibit its function
� In conclusion, the data demonstrate that the prosurvival Bcl-2 family of proteins does not directly
regulate autophagy, but any impact they have on autophagy is indirect, via Bax and Bak activation
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It is widely accepted that Bcl-2 not only inhibits apoptosis but also
negatively regulates autophagy by binding to Beclin 1.
We provide genetic and biochemical evidence that the effects of
Bcl-2 on autophagy are instead an indirect consequence of its
inhibition of apoptosis mediators Bax and Bak.
We show that in the absence of Bax and Bak, antagonizing or
altering the levels of Bcl-2 has no detectable impact on autophagy.
Because several inhibitors of both autophagy and Bcl-2 are in
clinical trials for the treatment of cancer, it is important to
understand the cross-talk between these pathways.
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