Homeostasis, Regeneration and Cancer of the Adult Pancreas and Intestines
The Function of Sox17 in the Adult Pancreas
We have observed that adult endodermal organs continue to express many embryonic factors. However, the function of these factors in adult cell homeostasis and their involvement in organ dysfunction and disease remain poorly understood. For example, the transcription factor Sox17 is a key regulator of endoderm and it is expressed in the adult pancreas, lung and intestine; however, its function in the adult is largely unknown.We have used two antibodies, QRT-PCR, and microarray analysis to demonstrate that Sox17 is expressed in the developing and adult endocrine pancreas (figure 1A). Sox17 protein is detected in virtually all beta and alpha cells and Pdx1-expressing cells and at lower levels in a subset of acinar cells and endothelial cells. We investigated the role of Sox17 in cases of beta cell dysfunction by using a tetracycline inducible transgenic approach to overexpress Sox17 in the beta cells of hyperglycemic animals. We find that animals in which we have upregulated Sox17 for seven days have normal blood sugar levels, comparable to control animals (not shown).
The above data suggest that Sox17 can improve beta cell function and reverse hyperglycemia. We next used this genetic approach to investigate the role of Sox17 during beta cell injury. We used a low-dose streptozotocin (STZ) protocol where 50mg / kg STZ was injected IP for five consecutive days, resulting in severe hyperglycemia, reduced beta cell numbers and disrupted islet architecture (figure 1B, upper right panel). In contrast, Sox17-overexpressing animals injected with STZ retained relatively normal beta cell function as measured by glucose levels, and islets were histologically comparable to control animals (figure 1B, lower right panel). These data strongly indicate that elevated Sox17 levels are beneficial for beta cell function and survival during increased metabolic demand and injury. The Pdx1-tTA null allele was generated in the lab of Ray MacDonald, UT Southwestern), and the Otet-Sox17-IRES-GFP responder lines were generated in the Wells lab.
The Role of Sox17 Intestinal Cell Homeostasis and Cancer: Sox Factors as Modulators of Wnt Signaling Activity
The canonical Wnt pathway is necessary for gut epithelial cell proliferation, and its aberrant activation causes intestinal neoplasia. We report a novel mechanism by which the Sox family of transcription factors regulates the canonical Wnt signaling pathway. We find that some Sox proteins antagonize while others enhance b-catenin / TCF activity. Sox17, which is expressed in normal gut epithelium but is reduced in intestinal neoplasias, is antagonistic to Wnt signaling. When overexpressed in SW480 colon carcinoma cells, Sox17 represses b-catenin / TCF activity in a dose-dependent manner and inhibits proliferation. In contrast, Sox4 is expressed in a mutually exclusive domain to Sox17 in normal and neoplastic gut tissue, and gain- and loss-of-function studies demonstrate that Sox4 enhances b-catenin / TCF activity and proliferation of SW480 cells. In addition to binding b-catenin, both Sox17 and Sox4 physically interact with TCF / LEF family members via their respective HMG box domains. Gain- and loss-of-function experiments suggest that the interaction of Sox proteins with b-catenin and TCF / LEF proteins regulates their stability. In particular, Sox17 promotes degradation of both b-catenin and TCF proteins via a noncanonical, GSK3b-independent mechanism that can be blocked by proteasome inhibitors. In contrast, Sox4 may function to stabilize b-catenin protein. These findings indicate that Sox proteins can act as both antagonists and agonists of b-catenin / TCF activity, and this mechanism may regulate Wnt signaling responses in many developmental and disease contexts.
