Proteins, like people, can be complex and mysterious -- at least to the scientists studying them. Some two decades after discovering adenomatous polyposis coli (APC), researchers are still puzzling out this particular protein's secrets. They do know that APC is critical in protecting against colon cancer: in approximately 80 percent of cases, the gene for APC is mutated either sporadically or through germline inheritance.
Kristi Neufeld, Ph.D., co-leader of Cancer Biology, has spent the better part of her career so far following APC's tracks, unearthing a few more prints along the way. She and her laboratory group have found that certain APC functions seem to depend on location -- the protein normally shuttles between a cell's control center, otherwise called the nucleus; and its surrounding gel-like cytoplasm. Whether APC reaches the nucleus may well affect the ability of intestinal stem cells to differentiate into other cell types with specialized functions, Neufeld proposes.
"It's not widely appreciated, but there is still plenty of cell growth going on in adults, with the colon being a good example," she says. "On average, we shed and replace about 70 pounds of intestinal tissue yearly, so you can imagine that this process requires exquisite control to prevent tumor formation."
Regular renewal of the colon lining occurs through stem cells that are capable of constantly dividing. These cells produce descendants that take up specific roles: by secreting mucin, for instance, goblet cells generate the mucus layer that serves as the colon's sole physical barrier against its many microbial tenants. But if APC can't find its way to the nucleus, Neufeld and her team have noted far fewer goblet cells as one outcome.
"We introduced a specific APC mutation into mice that took away the nuclear zip code, so to speak, leaving APC stuck in the cytoplasm," Neufeld explains. The researchers studied this mouse model under conditions that induce ulcerative colitis, a form of inflammatory bowel disease that can be a prelude to colon cancer. 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 crew may have a clue as to how this happens.
"The drop in goblet cell numbers we observed was striking," she says. "We then examined one of the proteins found in mucin, 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 mucin, which could increase the colon's sensitivity to bacteria and other microorganisms in the gut that are capable of promoting inflammation."
Thinking ahead clinically, Neufeld adds, 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 highly plausible, and the researchers probing possible mechanisms, they want to know if and how Wnt pathway members might be involved.
"We are looking at two theories," Neufeld says. "The first is that APC physically binds to β-catenin in the nucleus, preventing the latter from being an aide in the transcription of other important Wnt pathway genes. Or APC could bring collaborators into the nucleus -- basically, other proteins that help repress transcription. Either way, if the nucleus is out of bounds for APC, intestinal stem cells will keep dividing when they should be differentiating into specific types such as goblet cells."
Comprising 2843 amino acids, APC is no small representative of proteins in general. "APC is more like a complex of moving parts, each doing something different and most still poorly understood," Neufeld says. "I think if the sole purpose of this protein was to target β-catenin for destruction, it wouldn't need to be this large. So even if we find that Wnt signaling, as mediated through APC, is not involved in our latest observation, it's still likely that goblet cell differentiation is controlled by one or more of APC's many components."
Beyond a slew of mechanistic details, the bigger picture that Neufeld and her group will keep exploring is that some colon cancers could arise from an inflammatory response to bacterial penetration of a thinner than normal mucus layer in the gut, resulting from defective APC. The possibilities of just what APC does and doesn't do, and how to compensate for any intestinal glitches related to this protein's shortcomings, present a challenging mystery but also a plentiful harvest for scientists to reap.
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