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Multi-subunit translation elongation factor 1 in health and carcinogenesis

Project information

Grant agreement ID: INTAS2005-1000004-7750

  • Start date

    1 April 2006

  • End date

    30 September 2008

Funded under:

IC-INTAS

  • Overall budget:

    € 140 000

  • EU contribution

    € 120 000

Coordinated by:

INSTITUTE OF BIOCHEMISTRY AND BIOPHYSICS

Poland

Objective

Human translation elongation factor 1 (eEF1) consists of four subunits. The main function of the eEF1 complex is to supply correct aminoacyl-tRNA to A site of programmed 80S ribosome in GTP-dependent way and, after this, to re-charge the eEF1A molecule with GTP. Besides, the eEF1A2 isoform is an oncogene in ovary cancer, eEF1A1 and eEF1Bb enhance the ability of carcinogens to induce transformation in human cells. mRNA for eEF1A and eEF1B? ?are overexpressed in cancer cell lines and tumours. Cancer-related increase of the translation elongation rate could be directly coupled with changes in the amount and/or activity of elongation factors. Also, the number of non-translational eEF1A-involving processes, such as cytoskeleton interactions or inhibition of apoptotic processes, could be related to oncogenic properties of eEF1A. The main idea of the project is that alteration of activity of eEF1 during carcinogenesis could be influenced by both overexpression of the eEF1 subunits and their differential posttranslational modification (PTM) status. Noteworthy, high level of eEF1A phosphorylation was found recently by the Uppsala team in MCF7 cancer cells. Having in hand preparative quantities of all components of the eEF1 complex and utilizing a number of functional tests combined with potent MS approach we should be able to decipher how tumour-related PTMs influence eEF1 functioning during malignancy processes. The objectives of the project are: 1. Investigation of the expression of different subunits of eEF1 at the level of protein and mRNA in tumours of different origin and localization. 2. Examination whether tumour-related overexpression of the eEF1 subunits is coupled with alteration of their PTM. Identification of the tumour-related PTM sites in the eEF1 subunits by mass-spectroscopic methods. Production of mutants of eEF1A to mimic or to abrogate cancer-related PTM found by MS. 3. Disclosing the effect of PTM in eEF1A and eEF1B on their activity: i) examination of the effect of tumour-related phosphorylation and other PTM of eEF1A in different functional tests, including translation errors analysis, interaction of eEF1A with actin and calmodulin; ii) study of the effect of the tumour-related PTM on the GDP/GTP exchange activity of the eEF1B subunits and their functioning in translation. We expect to obtain novel experimental information about expression of eEF1 subunits at the level of a protein in human tumours of different origin and localization. The level and nature of the tumour-related PTM will be determined. Will be disclosed the effect of cancer-related modifications on the translational activity of the eEF1 complex and on the ability of eEF1A to interact with non-translational ligands involved in cell regulation and cytoskeleton organization. The understanding of the alteration of the eEF1 subunits expression and/or PTM specific for certain types of cancer would imply the clinical significance of eEF1 and PTM-specific antibodies.

Coordinator

INSTITUTE OF BIOCHEMISTRY AND BIOPHYSICS

Address

Pawinskiego, 5a
Warsaw

Poland

Participants (2)

INSTITUTE OF MOLECULAR BIOLOGY AND GENETICS OF NASU

Ukraine

UPPSALA UNIVERSITY

Sweden

Project information

Grant agreement ID: INTAS2005-1000004-7750

  • Start date

    1 April 2006

  • End date

    30 September 2008

Funded under:

IC-INTAS

  • Overall budget:

    € 140 000

  • EU contribution

    € 120 000

Coordinated by:

INSTITUTE OF BIOCHEMISTRY AND BIOPHYSICS

Poland