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doctoral thesis
Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2
2008. urn:nbn:hr:171:916562
Marinović Terzić, Ivana
University of Split
School of Medicine

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Marinović Terzić, I. (2008). Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2 (Doctoral thesis). Split: University of Split, School of Medicine. Retrieved from https://urn.nsk.hr/urn:nbn:hr:171:916562

Marinović Terzić, Ivana. "Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2." Doctoral thesis, University of Split, School of Medicine, 2008. https://urn.nsk.hr/urn:nbn:hr:171:916562

Marinović Terzić, Ivana. "Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2." Doctoral thesis, University of Split, School of Medicine, 2008. https://urn.nsk.hr/urn:nbn:hr:171:916562

Marinović Terzić, I. (2008). 'Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2', Doctoral thesis, University of Split, School of Medicine, accessed 20 November 2024, https://urn.nsk.hr/urn:nbn:hr:171:916562

Marinović Terzić I. Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2 [Doctoral thesis]. Split: University of Split, School of Medicine; 2008 [cited 2024 November 20] Available at: https://urn.nsk.hr/urn:nbn:hr:171:916562

I. Marinović Terzić, "Defekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2", Doctoral thesis, University of Split, School of Medicine, Split, 2008. Available at: https://urn.nsk.hr/urn:nbn:hr:171:916562

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Metadata
TitleDefekt apoptotskog odgovora na cisplatinu uzrokovan R20Q varijantom proteina PMS2
Title (english)Defect in the apoptotic response to cisplatin caused by the R20Q variant of the PMS2 protein
AuthorIvana Marinović Terzić
MentorJanoš Terzić (mentor)
Committee memberEduard Vrdoljak (predsjednik povjerenstva)
Committee memberSnježana Tomić (član povjerenstva)
Committee memberBranko Dmitrovic (član povjerenstva)
GranterUniversity of Split
School of Medicine
Split
Defense date and country2008, Croatia
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Basic Medical Sciences
Human Genetics, Genomics and Proteomics
Universal decimal classification
(UDC)		61 - Medical sciences
Abstract
Popravljači pogrešno sparenih baza (MMR) obavljaju popravak replikacijskih pogrešaka nastalih tijekom DNA sinteze. Isto tako, MMR proteini kod sisavaca imaju sposobnost aktivacije kontrolne točke staničnog ciklusa, te pokretanja apoptoze kao odgovora na nepopravljivo oštećenje DNA. Stanice s manjkavošću MMR sustava otporne su na djelovanje cisplatine - kemoterapeutika koji uzrokuje interlančano, unakrsno povezivanje nukleotida, i to zbog poremećene aktivacije apoptotskog puta. Od prije je poznato da je PMS2 protein, jedan od proteina iz MMR skupine, neophodan za aktivaciju proteina p73 nakon oštećenja DNA cisplatinom. Protein p73 je član porodice p53, s kojim dijeli proapoptotsku aktivnost. Humani PMS2 protein je izrazito polimorfan; definirano je barem dvanaest zamjena aminokiselina. U ovom radu pokazali smo defekt varijante R20Q-PMS2 u poticanju apoptotskog odgovora na cisplatinu putem aktivacije proteina p73. Kada je izražen u mišjim fibroblastima bez endogenog PMS2 proteina, varijanta R20Q-PMS2, u usporedbi s divljim tipom proteina PMS2, izaziva slabiji apoptotski odgovor na cisplatinu. Isto tako, citotoksični učinak cisplatine, mjeren testom klonskog preživljenja, pojačan je kod PMS2, ali ne i kod PMS2-R20Q. Budući je kod PMS2-R20Q oštećena pro-apoptotska aktivnost, ovaj varijanta PMS2 proteina možda ima ulogu u moduliranju tumorskog odgovora na cisplatinu kod liječenja pacijenata sa zloćudnim tumorima.
Abstract (english)
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 pro-apoptotic activity, this PMS2-polymorphic allele may play a role in modulating the tumor response to cisplatin among cancer patients.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:171:916562
Study programmeTitle: Basic and clinical medical sciences
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstva, polje kliničke medicinske znanosti (doktor/doktorica znanosti, područje biomedicine i zdravstva, polje kliničke medicinske znanosti)
Type of resourceText
File originBorn digital
Access conditionsOpen access
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Created on2024-04-24 08:23:53