Proteina tumorale p53

La proteina p53, modulata dal gene TP53 collocato sul cromosoma 17 esattamente in 17p13.1, regola la crescita e la divisione cellulare e riveste un ruolo importante nell’arresto della proliferazione delle cellule anormali e quindi nello sviluppo di neoplasie. E’ detta anche Antigene tumorale cellulare p53, Soppressore tumorale p53, Fosfoproteina p53, Antigene NY-CO-13, Oncosoppressore p53. E’ stata identificata nel 1979 da 6 gruppi di ricercatori:  DeLeo et al. 1979, Kress et al. 1979, Lane & Crawford 1979, Linzer & Levine 1979, Melero et al. 1979, Smith et al. 1979. E’ composta da 393 aminoacidi e deve il suo nome alla sua massa molecolare: pesa infatti 53 kDa (1-10). 

Meccanismo d’azione: la proteina p53 interviene con diversi meccanismi:

• attiva la riparazione del DNA danneggiato (se il DNA è riparabile), inducendo la trascrizione di geni riparatori del DNA come GADD45;
• in seguito a danni del DNA p53 viene fosforilata da ATM e in tale forma può agire come fattore di trascrizione, migra nel nucleo, si lega a p21 inducendone la trascrizione e portando così al blocco del ciclo cellulare inibendo il complesso cdk4-cdk6/ciclina D;
• in caso di danno irreparabile, può dare inizio all’apoptosi, inducendo la trascrizione di Noxa
• se il DNA viene riparato, la proteina p53 viene degradata da MDM2 e quindi  c’è la ripresa del ciclo cellulare.

Può dunque indurre l’arresto della crescita cellulare, l’apoptosi e la senescenza cellulare (11-23).

La p53 partecipa all’apoptosi neuronale da malattie neurodegenerative come la sclerosi multipla, la corea di Huntington, la malattia di Alzheimer, la malattia di Parkinson e la sclerosi laterale amiotrofica. Dunque delle molecole che preverrebbero l’attivazione o l’attività di p53 in queste malattie neurologiche, potrebbero costituire dei farmaci di estremo beneficio per rallentare la loro progressione (23-38).

Mutazioni del gene PT53  sono state osservate in molti pazienti affetti da neoplasie. Tali mutazioni compromettono la funzionalità del gene e annullano le proprietà oncosoppressive della proteina p53.   I pazienti neoplastici che possiedono mutazioni a livello del gene PT53 hanno una prognosi sfavorevole della malattia rispetto ai pz. in cui il gene è normale. La caratterizzazione delle mutazioni del gene PT53, su cellule cancerose o normali, mediante il sequenziamento automatico a tecnologia fluorescente del DNA può essere quindi impiegata come marker per l’outcome terapeutico e come rivelatore di rischio neoplastico (39,40).

Cercare di ripristinare la funzionalità del gene sarebbe un ulteriore passo avanti per la cura di molte neoplasie e malattie degenerative (41).

MDM2 è una oncoproteina sovraespresso in vari tipi di neoplasie.  La sua funzione primaria è quella di inibire l’attività della proteina p53 nell’ottica di una condizione di equilibrio funzionale intesa a modulare l’azione della proteina p53 limitandone l’azione in caso di necessità. MDM2 favorisce la degradazione cellulare e l’apoptosi oppure la ripresa del ciclo mitotico a seconda delle situazioni (52-59). La sua secrezione è modulata dalla stessa proteina p53 (42-52).

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