| First Author | Chandrakesan P | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 11 | Pages | e79432 |
| PubMed ID | 24278135 | Mgi Jnum | J:209657 |
| Mgi Id | MGI:5568284 | Doi | 10.1371/journal.pone.0079432 |
| Citation | Chandrakesan P, et al. (2013) Differential effects of beta-catenin and NF-kappaB interplay in the regulation of cell proliferation, inflammation and tumorigenesis in response to bacterial infection. PLoS One 8(11):e79432 |
| abstractText | Both beta-catenin and NF-kappaB have been implicated in our laboratory as candidate factors in driving proliferation in an in vivo model of Citrobacter rodentium (CR)-induced colonic crypt hyper-proliferation and hyperplasia. Herein, we test the hypothesis that beta-catenin and not necessarily NF-kappaB regulates colonic crypt hyperplasia or tumorigenesis in response to CR infection. When C57Bl/6 wild type (WT) mice were infected with CR, sequential increases in proliferation at days 9 and 12 plateaued off at day 19 and paralleled increases in NF-kappaB signaling. In Tlr4(-/-) (KO) mice, a sequential but sustained proliferation which tapered off only marginally at day 19, was associated with TLR4-dependent and independent increases in NF-kappaB signaling. Similarly, increases in either activated or total beta-catenin in the colonic crypts of WT mice as early as day 3 post-infection coincided with cyclinD1 and c-myc expression and associated crypt hyperplasia. In KO mice, a delayed kinetics associated predominantly with increases in non-phosphorylated (active) beta-catenin coincided with increases in cyclinD1, c-myc and crypt hyperplasia. Interestingly, PKCzeta-catalyzed Ser-9 phosphorylation and inactivation of GSK-3beta and not loss of wild type APC protein accounted for beta-catenin accumulation and nuclear translocation in either strain. In vitro studies with Wnt2b and Wnt5a further validated the interplay between the Wnt/beta-catenin and NF-kappaB pathways, respectively. When WT or KO mice were treated with nanoparticle-encapsulated siRNA to beta-catenin (si-beta-Cat), almost complete loss of nuclear beta-catenin coincided with concomitant decreases in CD44 and crypt hyperplasia without defects in NF-kappaB signaling. si-beta-Cat treatment to Apc(Min/+) mice attenuated CR-induced increases in beta-catenin and CD44 that halted the growth of mutated crypts without affecting NF-kappaB signaling. The predominant beta-catenin-induced crypt proliferation was further validated in a Castaneus strain (B6.CAST.11M) that exhibited significant crypt hyperplasia despite an attenuated NF-kappaB signaling. Thus, beta-catenin and not necessarily NF-kappaB regulates crypt hyperplasia in response to bacterial infection. |
