Observing significantly more colon tumors in these mice compared to those with normal APC in the same disease setting, they hypothesized that functional nuclear APC might somehow guard against inflammation and its downstream effects, including tumor development. Now, Neufeld thinks she and her team may have a clue as to how this happens.
"The drop in goblet cell numbers we observed was striking," she said. "We then examined one of the proteins found in mucus, called Muc2, and found that its RNA levels were greatly decreased. If there are fewer goblet cells as a result of APC being unable to reach the nucleus, there will also be less mucus, which could increase the colon's sensitivity to bacteria and other microorganisms in the gut that are capable of promoting inflammation."
Neufeld said while there are still no quick fixes for mutant genes, perhaps tools could be developed to synthetically replace this less-than-ideally thick mucus layer in affected people.
One known function of APC is that it halts cell proliferation: by muzzling the canonical arm of the Wnt signaling pathway, which otherwise instructs cells to go forth and multiply. Neufeld and her group have already shown, using the same mouse model, that APC stationed in the nucleus is necessary to suppress Wnt and its signaling partners particularly β-catenin, a key target of normal APC. With a role for nuclear APC in controlling goblet cell differentiation now supported, the researchers are probing possible mechanisms to learn if and how Wnt pathway members might be involved.
Comprising 2,843 amino acids, APC is a large protein.
"Rather than being a simple, single-function protein, APC is more like a complex set o
|Contact: Brendan M. Lynch|
University of Kansas