AKME · The physiological role of E2F1 acetylation: a gene targeting approach
6РП — Действия „Мария Кюри“
- Период
- 2006-03-15 → 2009-03-14
- Финансиране от ЕС
- 258 172 €
- Участници
- 2
- Схема
- OIF
Линиите свързват координатора с партньорите.
Накратко на български
Взаимодействието между протеините pRB и E2F1 и тяхната модификация чрез ацетилиране се проучват чрез мишарски модели и клетъчни тестове. Това помага за разбирането на развитието на тумори и начина, по който клетките реагират или се съпротивляват на химиотерапията.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - AKME (The physiological role of E2F1 acetylation: a gene targeting approach)
PRB is one of the most important tumour suppressive proteins which, since its discovery, has been a focal point of cancer research. At a molecular level, pRB exerts its functions through the interaction with the E2F1 protein. The resulting pRB-E2F1 protein complex regulates the expression of genes relevant to cellular growth and cell death. Alterations of pRB-E2F1 activity have been implicated in a wide variety of tumours. Dr Ianari applied a combination of in vitro, i.e. cellular-based, and in vivo, i.e. mouse-based, approaches to study the mechanisms that regulated the function of the pRB-E2F1 complex in response to deoxyribonucleic acid (DNA) damaging insults, such as chemotherapeutic agents and ionising radiations. The results of these studies indicated that pRB could arrest cellular proliferation or promote cell death in response to genotoxic stress, through the regulation of E2F1 activity. The studies also suggested that a modification of pRB and E2F1, named acetylation, was important to regulate the formation of the pRB-E2F1 complex and therefore its tumour suppressive activities in the DNA damage response. Based on these results Dr Ianari decided to expand her studies through the generation of two mouse models to allow for the re-expression of the pRB or the E2F1 mutant proteins. These models would allow the unequivocal in vivo validation of the role of the pRB-E2F1 complex acetylation during tumourigenesis as well as in the response and resistance to chemotherapeutic drugs, thus facilitating the design of new therapeutic tools.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
To complete and diversify her scientific expertise, Dr. Ianari has decided to join Dr. Lees' lab, a leading lab located in a top-level research organization (MIT¿ USA). The aim of her project is to study the role of E2F1 acetylation in the DNA damage response and in the development and homeostasis of the normal tissues. E2F1 is a transcriptional factor that possess both oncogenic and tumour suppressive functions. The spectrum of E2F1-regulated genes is quite large and comprises genes involved in the regulation of development, differentiation, cell cycle progression and apoptosis. Dr. Ianari has recently demonstrated that DNA damage specifically activates E2F1 apoptotic potential in an acetylation-dependent manner by the selective relocalization of transcriptionally active E2F1 from cell cycle genes to the promoter of the proapoptotic p73 gene. Indeed, E2F1 acetylation is the main determinant of the outcome of E2F1 activity in response to DNA damage. Whether this pathway is specifically restricted to maintain tissue homeostasis in the presence of unrepairable DNA damage, or is involved in additional cell regulatory functions, is presently unknown.The aim of this project is to use a gene targeting approach to generate a mouse strain that produces a version of E 2F1 that cannot be acetylated but is otherwise regulated physiologically. Dr. Ianari will combine highly innovative and sophisticated techniques (knock-in mouse model generation, chromatin immuno-precipitation and micro-array analysis) and multidisciplinary approaches (developmental biology, molecular biology and experimental oncology), to provide insight into the underlying mechanisms of tumour development that will aid the development of new selective cancer therapies. This experience will advance Dr. Ianari' s independent career development in two ways: she will gain additional knowledge both in scientific and technological terms, and it will provide her with long-lasting scientific collaborations.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITY OF ROME LA SAPIENZA"" · ROMAКоординаторИталия
- MASSACHUSETTS INSTITUTE OF TECHNOLOGY · CAMBRIDGEСъединени щати
Връзки
Данни: CORDIS, © Европейски съюз