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La via apoptotica intrinseca
Lo stress cellulare interno, come danno cellulare o ipossia, innesca l’apoptosi intrinseca. La famiglia di proteine del linfoma a cellule B 2 (Bcl-2)…
La via apoptotica intrinseca è attivata da segnali di morte intracellulari, come lo stress ossidativo e il danno al DNA.
Nei mammiferi, la via è regolata dalla famiglia di proteine Bcl-2, che ha membri della famiglia sia pro che anti-apoptotici.
Leproteine proapoptotiche includono le proteine solo BH3, come Bad e Bim, e le proteine effettrici della famiglia Bcl-2, come Bax e Bak. Le proteine anti-apoptotiche includono Bcl-XL e Bcl-2 e inibiscono l'attività di Bax e Bak.
I segnali di morte attivano le proteine BH3-only, che possono inattivare le proteine anti-apoptotiche o legarsi direttamente alle proteine effettrici.
In entrambi i casi, questi effettori oligomerizzano sulla membrana mitocondriale e formano pori che rilasciano citocromo c.
Il citocromo c si lega al fattore di attivazione della proteasi apoptotica-1, ai monomeri Apaf-1 e Apaf-1 e si assembla in un complesso eptamerico, chiamato apoptosoma.
Successivamente, l'iniziatore procaspasi-9 si lega all'apoptosoma e dimerizza, formando la caspasi-9.
Infine, la caspasi-9 attiva le caspasi carnefici che scindono le proteine cellulari, provocando l'apoptosi.
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Q1: What intracellular signals trigger the intrinsic apoptotic pathway?
The intrinsic apoptotic pathway is activated by intracellular death signals, including oxidative stress and DNA damage. When DNA damage occurs, checkpoint proteins like ATM and Chk2 are activated, which phosphorylate p53 and trigger pro-apoptotic responses. These internal cellular stressors, such as cellular injury or hypoxia, initiate the cascade leading to programmed cell death.
Q2: How do Bcl-2 family proteins regulate the intrinsic apoptotic pathway?
The Bcl-2 family contains both pro-apoptotic and anti-apoptotic members that balance cell survival and death. Pro-apoptotic proteins like Bax, Bak, and BH3-only proteins activate apoptosis, while anti-apoptotic proteins like Bcl-XL and Bcl-2 inhibit them. Death signals activate BH3-only proteins, which either inactivate anti-apoptotic proteins or directly bind effector proteins to initiate the pathway.
Q3: What happens when Bax and Bak proteins oligomerize on the mitochondrial membrane?
When Bax and Bak oligomerize on the mitochondrial membrane, they form pores that release cytochrome c into the cytoplasm. Cytochrome c then binds to Apaf-1, triggering assembly of a heptameric complex called the apoptosome. This structure recruits and activates procaspase-9, which becomes caspase-9 and initiates the executioner caspase cascade.
Q4: What is the role of the apoptosome in the intrinsic apoptotic pathway?
The apoptosome is a heptameric complex formed when cytochrome c binds to Apaf-1 monomers and they assemble together. This structure serves as a platform that recruits and activates the initiator procaspase-9, converting it to active caspase-9. Caspase-9 then activates executioner caspases that cleave cellular proteins, resulting in apoptosis.
Q5: How is the intrinsic apoptotic pathway disrupted in cancer cells?
Cancer cells often have mutations that inhibit the intrinsic apoptotic pathway. Overexpression of anti-apoptotic proteins like Bcl-2 prevents cell death, while inhibitor of apoptosis proteins (IAPs) inactivate caspase-9. These alterations allow damaged cells to survive when they should undergo apoptosis, contributing to tumor development and progression.
Q6: What anti-cancer drugs activate the intrinsic apoptotic pathway?
Several anti-cancer drugs have been developed to reactivate the intrinsic apoptotic pathway in cancer cells. Molecules like Nutlin-2 and MI-219 inhibit MDM2 binding to p53, preventing p53 inactivation and promoting apoptosis. Other drugs such as SH122, JP1201, and YM155 inhibit IAPs and activate caspases, initiating apoptosis in cancer cells.
Q7: How does p53 activation lead to apoptosis during DNA damage?
During DNA damage, checkpoint proteins ATM and Chk2 phosphorylate p53, activating it as a transcription factor. p53 then activates pro-apoptotic proteins such as Bax, Bak, PUMA, and Noxa while inhibiting anti-apoptotic proteins like Bcl-2 and Bcl-XL. This coordinated shift in Bcl-2 family protein balance triggers the mitochondrial pathway, leading to apoptosis of damaged cells.