Functional characterization of the protein and its role in cellular proliferation and leukemogenesis

Resumo

CATS is the CALM (PICALM) interacting protein expressed in thymus and spleen. The CATS interaction region of CALM is contained in the leukemogenic fusion protein CALM/AF10, which is found in AML, ALL and in malignant lymphoma. CATS sequesters CALM/AF10 in the nucleolus and interferes with the transactivation capacity of CALM/AF10 in a dose-dependent manner. However, the involvement of CATS in malignant transformation seems to go beyond its interaction with the CALM/AF10. CATS is highly expressed in leukemia, lymphoma and tumor cell lines but not in non-proliferating T-cells or PBLs. Protein levels are cell cycle-dependem and induced by mitogens (e.g. PHA). The upregulation of CATS upon mitogenic activation and its high expression in proliferating but not in quiescent cells, as well as its nucleolar localization, suggest a role of CATS in the control of cell proliferation. Several CATS interacting proteins were identified, including SIVA-1, a pro-apoptotic protein. Recently, we have shown that SIVA-1 also associates with ANKHD1 (Ankyrin Repeat and KH domain containing 1). Similarly to CATS, ANKHD1 is highly expressed in leukemia cell lines suggesting a role for this protein in leukemogenesis. The fact that CATS and ANKHD1 are highly expressed in leukemia cell lines and are both involved in protein interaction with SIVA-1, indicate that these proteins might be involved in the same regulatory pathway contributing to malignant transformation. The aim of this project is to investigate to which extent CATS contributes to or determines cell proliferation and what effect its depletion or overexpression might have on myelodysplastic, leukemic and tumor cells. Moreover we aim to analyze CATS interaction with its partner proteins. This work will provide valuable insights into regulatory networks in which CATS might be involved and that are key pathways involved in tumorigenesis. (AU)