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Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2 : doktorska disertacija

Fakulteti, doktorske disertacije Vrsta gradje
Naslov
Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2 : doktorska disertacija / Ivana Marinović Terzić ; [voditelj rada Janoš Terzić]. -
Impresum
Split : I. Marinović Terzić, 2008. ([s. l. : s. n.]). -
Materijalni opis
56 listova : graf. prikazi (djelomice u bojama) ; 30 cm + 1 optički disk. -
Uputnica
Jezik
hrv, eng
Napomena
Na vrhu nasl. str.: Sveučilište u Splitu, Medicinski fakultet.
Bibliografija: listovi 47-52. Summary.

SUMMARY

Mismatch repair (MMR) corrects replication errors during DNA synthesis.
The mammalian MMR proteins also activate cell cycle checkpoints and apoptosis in response to persistent DNA damage. MMR-deficient cells are resistant to cisplatin -a DNA crosslinking agent used in chemotherapy, due to impaired activation of apoptotic pathways.
It is previously shown that PMS2, an MMR protein, is required for cisplatin-induced activation of p73, a member of the p53-family with pro-apoptotic activity.
The human PMS2 gene is highly polymorphic; at least twelve nonsynonymous codon changes have been identified.
We show here that the PMS2-R20Q variant is deficient in activating p73-dependent apoptotic response to cisplatin.
When expressed in Pms2-deficient mouse fibroblasts, human PMS2-R20Q, but not PMS2, reduced the apoptotic response to cisplatin.
Correspondingly, the cytotoxic effect of cisplatin, measured by clonogenic survival, is enhanced by PMS2 but not PMS2-R20Q. Because PMS2-R20Q lacks the proapoptotic activity, this PMS2-polymorphic allele may play a role in modulating the tumor response to cisplatin among cancer patients.

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