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

• Grant number: 07/08019-1
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): March 01, 2008
• Effective date (End): February 28, 2011
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Sara Teresinha Olalla Saad
• Grantee: Leticia Fröhlich Archangelo
• Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 05/51681-1 - Functional investigation and characterization of the involvement of novel target genes and new therapeutics for myelodysplastic and leukemia lineages, AP.TEM

Abstract

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 acute myeloid leukemia (AML), acute lymphoblastic leukemia (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 CALM/AF10. CATS is highly expressed in leukemia, lymphoma and tumor cell lines but not in non-proliferating T-cells or peripheral blood lymphocytes (PBLs). The protein level of CATS are cell cycle-dependent 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, Traina and coworkers have shown that SIVA-1 also associates with ANKHD1 (Ankyrin Repeat and KH domain containing 1) (Projeto Temático 05/51681-1). Similarly to CATS, ANKHD1 is highly expressed in leukemia cell lines which suggests 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 the interaction of CATS with its partner proteins. This work will provide valuable insights into the regulatory networks in which CATS is involved, which might be key pathways of tumorigenesis. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ARCHANGELO, LETICIA FROEHLICH; GREIF, PHILIPP A.; MAUCUER, ALEXANDRE; MANCEAU, VALERIE; KONERU, NARESH; BIGARELLA, CAROLINA L.; NIEMANN, FERNANDA; DOS SANTOS, MARCOS TADEU; KOBARG, JOERG; BOHLANDER, STEFAN K.; OLALLA SAAD, SARA TERESINHA. The CATS (FAM64A) protein is a substrate of the Kinase Interacting Stathmin (KIS). BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1833, n. 5, p. 1269-1279, MAY 2013. Web of Science Citations: 8.

BIGARELLA, CAROLINA L.; VIEIRA FERRO, KARLA P.; BARCELLOS, KARIN S. A.; MARTINS-DE-SOUZA, DANIEL; TRAINA, FABIOLA; NOVELLO, JOSE C.; OLALLA SAAD, SARA T.; ARCHANGELO, LETICIA FROEHLICH. Post-translational modification of the RhoGTPase activating protein 21, ARHGAP21, by SUMO2/3. FEBS Letters, v. 586, n. 19, p. 3522-3528, SEP 21 2012. Web of Science Citations: 6.

ARCHANGELO, LETICIA FROEHLICH; GREIF, PHILIPP A.; HOELZEL, MICHAEL; HARASIM, THOMAS; KREMMER, ELISABETH; PRZEMECK, GERHARD K. H.; EICK, DIRK; DESHPANDE, ANIRUDDHA JAYANT; BUSKE, CHRISTIAN; DE ANGELIS, MARTIN HRABE; OLALLA SAAD, SARA TERESINHA; BOHLANDER, STEFAN K. The CALM and CALM/AF10 interactor CATS is a marker for proliferation. MOLECULAR ONCOLOGY, v. 2, n. 4, p. 356-367, DEC 2008. Web of Science Citations: 11.