Research Lab
Vincent Yang M.D., Ph.D.
The primary research focus of Dr. Yang's lab is to understand the molecular mechanisms that regulate proliferation and differentiation of the mammalian intestinal epithelial cells. The intestinal epithelium is a dynamic system in which rapid proliferation of stem cells in the intestinal crypts is balanced by the shedding of cells from the tip of the intestinal villus into the lumen. As cells go through this transition, they stay differentiated for a period of time and carry out most of the housekeeping functions of the intestinal tract such as digestion and absorption (Figure 1). Our group has concentrated on investigating the roles played by a number of Krüppel-like transcription factors and the Wnt family of molecules in regulating two key biological processes in the gut epithelium, proliferation and differentiation.
Krüppel-like factors (KLFs) are zinc finger-containing transcription factors that exhibit homology to the Drosophila protein Krüppel, a key regulator of embryogenesis. In particular, we are investigating the functions of KLF4, expressed primarily in the post-mitotic, differentiated epithelial cells lining the villus border, and KLF5, expressed primarily in the proliferating crypt epithelial cells. In cultured cells, expression of KLF4 causes cell cycle arrest whereas expression of KLF5 leads to increased cell proliferation. We hypothesize that KLF4 and KLF5 are mediators for a larger network of regulators that control intestinal epithelial cell homeostasis. These regulators include the important tumor suppressor proteins APC and p53, and the protooncoproteins RAS and WNT. The knowledge derived from these studies may impact on the understanding of the mechanisms of gut development as well as the mechanism of intestinal tumorigenesis.
Figure 1. The gut epithelium as a dynamic model for studying the regulation of cell proliferation and differentiation.
The intestinal epithelium is consisted of proliferating and differentiated/non-proliferating cells. Stem cells reside near the bottom of the crypt and are capable of self-renewal and giving rise to descendant cells that are growth-arrested and differentiated. Cells migrate from the bottom of the crypt to the tip of the villus where they are shed in the lumen. The average life span of an epithelial cell from its birth to its death is about 3 days.
Lab Staff
Sengthong Chanchevalap (Lead Research Specialist)
James Du, Ph.D. (Lead Research Specialist)
Amr Ghaleb, Ph.D. (Postdoctoral Fellow)
Irfan Hisamuddin, M.D. (Post-doctoral Fellow)
Misuzu Hitomi (Lead Research Specialist)
Mandayam Nandan, M.S. (Lead Research Specialist)
Sharon Ngwenya, Ph.D. (Post-doctoral Fellow)
Erika Whitney, Ph.D. (Post-doctoral Fellow)
Brian Dalton (Student)
Representative Lab Publications:
Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW (2003) Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity. Oncogene 22(22): 3423-30.
Chen X, Whitney EM, Gao SY, Yang VW (2003) Transcriptional profiling of Krüppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation. J Mol Biol. 326(3):665-77.
Yoon HS, Chen X, Yang VW. (2003) Krüppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. J Biol Chem. 2003 278(4):2101-5.
Yang VW (2002) APC as a checkpoint gene: the beginning or the end? Gastroenterology. 123(3):935-9.
Katz JP, Perreault N, Goldstein BG, Lee CS, Labosky PA, Yang VW, Kaestner KH. (2002) The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development. 129(11):2619-28.
Giardiello FM, Yang VW, Hylind LM, Krush AJ, Petersen GM, Trimbath JD, Piantadosi S, Garrett E, Geiman DE, Hubbard W, Offerhaus GJ, Hamilton SR. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med. 346(14):1054-9.
Gala M, Sun R, Yang VW (2002) Inhibition of cell transformation by sulindac sulfide is confined to specific oncogenic pathways. Cancer Lett. 175(1):89-94.
Dang DT, Mahatan CS, Dang LH, Agboola IA, Yang VW (2001) Expression of the gut-enriched Kruppel-like factor (Kruppel-like factor 4) gene in the human colon cancer cell line RKO is dependent on CDX2. Oncogene 20(35):4884-4890.
Chen X, Johns DC, Geiman DE, Marban E, Dang DT, Hamlin G, Sun R, Yang VW (2001) Kruppel-like factor 4 (gut-enriched Kruppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. J. Biol. Chem. 276(32):30423-30428.
Sun R, Chen X, Yang VW (2001) Intestinal-enriched Kruppel-like factor (Kruppel-like factor 5) is a positive regulator of cellular proliferation. J. Biol. Chem. 276(10):6897-6900.
Dang DT, Pevsner J, Yang VW (2000) The biology of the mammalian Kruppel-like family of transcription factors. Int. J. Biochem. Cell Biol. 32(11-12):1103-1121.
Yang VW (1999) The molecular genetics of colorectal cancer. Curr. Gastroenterol. Rep. 1(5):449-454.