PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation...
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![Page 1: PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene.](https://reader036.fdocuments.net/reader036/viewer/2022062512/5542eb50497959361e8c0475/html5/thumbnails/1.jpg)
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PUMA
NOXA
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Dominant-negative missense p53 gene mutation
Upstream tumour suppressor gene mutation (ATM)
Oncogene amplification (MDM2)
Viral oncogene amplification (HPV E6)
INACTIVATION OF THE p53 PATHWAY
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Acetylation
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16201620
421421
240240
162042
1
240
162042
1
240
(A) wildtype or DNA contact mutants
(B) structural mutants
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STRATEGIE TERAPEUTICHE BASATE SU p53
TUMORI CHE PRESENTANO MUTAZIONI DI p53
terapia genica con p53 wildtype
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E1A
E1B
pRb
E1B 55kDa
E1B 19kDa
p53
ADENOVIRUSAPOPTOSI
DEGRADAZIONE
E1A
E1B
SOSTITUITI DA p53wt
rAd-p53
APOPTOSI
ARRESTOdel
CICLO CELLULARE
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PROBLEMI CONNESSI CON L’USO DI ADENOVIRUS
COME VETTORI PER LA TERAPIA GENICA
espressione genica transiente (14-21 gg)prevalenza di anticorpi neutralizzantiaccessibilità alle cellule tumorali
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STRATEGIE TERAPEUTICHE BASATE SU p53
TUMORI CHE PRESENTANO MUTAZIONI DI p53
terapia genica con p53 wildtype
virus oncolitici a replicazione selettiva (Onyx-015)
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E1A
E1B
pRb
E1B 55kDa
E1B 19kDa
p53
ADENOVIRUSAPOPTOSI
DEGRADAZIONE
E1A
E1BONYX-015
pRb
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STRATEGIE TERAPEUTICHE BASATE SU p53
TUMORI CHE PRESENTANO MUTAZIONI DI p53
terapia genica con p53 wildtype
virus oncolitici a replicazione selettiva (Onyx-015)
imitazione dei prodotti di geni regolati da p53
(p21waf1; Bax)
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STRATEGIE TERAPEUTICHE BASATE SU p53
TUMORI CHE PRESENTANO MUTAZIONI DI p53
terapia genica con p53 wildtype
virus oncolitici a replicazione selettiva (Onyx-015)
imitazione dei prodotti di geni regolati da p53
recupero farmacologico della proteina p53 mutata:
inibitori di Hsp90
altri
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PRIMA-1
(p53 reactivation and induction of massive apoptosis)
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STRATEGIE TERAPEUTICHE BASATE SU p53
TUMORI CHE PRESENTANO p53 wildtype
attivazione della risposta di p53
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STRATEGIE TERAPEUTICHE BASATE SU p53
TUMORI CHE PRESENTANO p53 wildtype
attivazione della risposta di p53
blocco dell’espressione di E6
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STRATEGIE TERAPEUTICHE BASATE SU p53
inibizione dell’espressione di Mdm2
inibizione della funzione di Mdm2
TUMORI CHE PRESENTANO p53 wildtype
attivazione della risposta di p53
blocco dell’espressione di E6
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STRATEGIE TERAPEUTICHE BASATE SU p53
blocco del trafficking nucleare di p53 (leptomicina B)
TUMORI CHE PRESENTANO p53 wildtype
attivazione della risposta di p53
blocco dell’espressione di E6
inibizione dell’espressione di Mdm2
inibizione della funzione di Mdm2
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pifithrin-