Teresa Frisan's Group
Our laboratory is interested in understanding the carcinogenic properties of chronic infection with CDT-producing bacteria. For this purpose, we need to understand several issues associated with CDT biology, such as toxin internalization, induction of genomic instability, tissue remodelling in in vitro and in vivo models, and characterization of survival signals activated by the intoxication.
Chronic inflammations and infections are associated with an increased risk for cancer development. However, the mechanisms by which bacterial infections contribute to carcinogenesis are poorly characterized. Chronic inflammation has been proposed as a key event in bacterial oncogenesis. However, accumulating evidence indicates that bacteria could also play a more direct role in the induction of DNA damage via the production of genotoxins that may enhance the tumor promoting effect of chronic inflammation. The best-characterized bacterial genotoxins are the cytolethal distending toxins (CDTs) produced by several Gram-negative bacteria, such as Escherichia coli and Salmonella enterica.
Active CDTs consist of three subunits: CdtA, CdtB and CdtC. The enzymatically active subunit, CdtB, shares structural and functional homology with mammalian deoxyribonuclease I (DNase I), while the CdtA and CdtC subunits contain ricin-like lectin domains that are involved in toxin internalization. Translocation of CdtB to the nucleus of intoxicated cells is accompanied by the induction of DNA double-strand breaks and triggering of an Ataxia telangiectasia mutated (ATM)-dependent DNA damage responses (DDR). Depending on the cell type and dose of toxin, the DDR response and its anti tumor activity is counteracted by the concomitant triggering of survival signals mediated by activation of the guanine nucleotide exchange factor Net1, the RhoA GTPase, and its down-stream effector p38 MAP kinase (MAPK).
Salmonella enterica delivers its genotoxin through outer membrane vesicles secreted from infected cells.
Cell. Microbiol. 2013 Dec;15(12):2034-50
Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response.
Cell. Microbiol. 2013 Jan;15(1):98-113
Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival.
J. Cell. Sci. 2011 Aug;124(Pt 16):2735-42
The ubiquitin C-terminal hydrolase UCH-L1 promotes bacterial invasion by altering the dynamics of the actin cytoskeleton.
Cell. Microbiol. 2010 Nov;12(11):1622-33