Teresa Frisan, PhD
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).
- Javier Avila-Cariño, Senior researcher and lab manager
- Riccardo Guidi, PhD Student
- Laura Levi, PhD Student
Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response.
Cell. Micro. 15, 98-113.
Ubiquitin C-terminal hydrolase-L1 interacts with adhesion complexes and promotes cell migration, survival, and anchorage independent growth.
FASEB J 26, 5060-70.
DNA damage triggers FEN1-dependent cytoskeleton remodeling and cell survival.
J of Cell Science, 124, 2735-2742.
Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage.
PLoS One, 5:e8924.
The ubiquitin C-terminal hydrolase UCH-L1 promotes bacterial invasion by altering the dynamics of the actin cyctoskeleton.
Cell Micro. 12, 1622-1633.