Eric Chang, Ph.D.
Department of Molecular and Cellular Biology (Lester and Sue Smith Breast Center)
Ph.D.: SUNY, Buffalo
Postdoctoral training: Cold Spring Harbor Lab
Ras GTPase Mediated Signal Transduction and Tumor Formation
Ras GTPases are biologically active when they are GTP-bound and inactive when they are GDP-bound. In response to cell signals, Ras proteins cycle between the GDP and GTP bound state, thus acting as binary switches that regulate a wide range of biological functions. Ras proteins play key roles in deciding whether a cell should divide or remain dormant or differentiate into another cell type. As the cancer cell frequently must tamper with these same programs that are controlled by Ras, mutations affecting Ras activities are among the most common genetic alterations in human tumors—approximately 30% of all human tumors contain ras mutations, and in some tumors, such as colon and pancreatic tumors, frequencies of ras mutations are as high as 50 and 90%, respectively.
My lab is pursuing two major goals in order to better understand how Ras controls tumorigenesis. Our first major endeavor is to identify novel Ras effectors, which are downstream targets controlled by Ras to regulate growth and differentiation. To this end, we are currently focusing on the Cdc42 pathway, which interacts with Int6, a potential tumor suppressor for breast cancer formation. Our results support a model in which Int6 can control tumor formation by regulating the functioning of the 26S proteasome, which acts to degrade mitotic regulatory proteins to ensure normal cell division control and chromosome stability. Our second project focuses on the fact that the human Ras pathways are very complex. There are four structurally similar Ras proteins that in vitro can activate many known Ras effectors; however, in vivo these Ras proteins appear to control different functions. Thus our second major goal is to decipher how a given Ras protein can selectively activate a particular effector in order to specifically control tumor formation. Our current model suggests that a given Ras protein can control different functions by signaling from different cell compartments, so that a Ras pathway functioning in one cell compartment can transform cells much more efficiently than that in another compartment.
We carry out these studies using modern molecular and genetic tools in a wide range of model organisms (see figure). We use the power of yeast genetics to efficiently identify new components whose functions are evolutionarily conserved, while mammalian cells, and particularly breast cancer cells are the ultimate arenas where our models can be tested.
Our model organisms: (A) and (B) are fission yeast, an organism that is most famous for the study of the cell cycle, for which Paul Nurse won the Nobel prize in 2001. Yeasts grow fast and can be easily manipulated by molecular genetics, thus making them efficient tools in dissecting complex molecular functions. In (A) are mutant cells (defective in ras and int6) that show abnormalities in chromosome segregation. Their chromosomes are stained blue (arrows), the spindle red, and the cell outline of one of the cells was marked to make it easy to see that the two sets of chromosomes in this cell are not attached to the spindle poles. One proteasome subunit in those cells in (B) is tagged by a red fluorescence protein, such that it is expressed from its authentic promoter. This type of tagging can be done in yeast in just one week. Proteasomes in yeast accumulate in the nuclear membrane, presumably because they are retained by nuclear proteasome substrates. We also use mammalian cells to more directly study tumor formation and signaling. Human mammary epithelial cells can be induced to polarize in vitro to form an ascinus (see panel C). These cells will form a ball and then those cells in the middle will undergo apoptosis to produce a hollow chamber, which resembles a mammary duct in vivo.
Baylor College of Medicine
One Baylor Plaza, Alkek N1110.01
Houston, TX 77030
- Sha Z, Brill LM, Cabrera R, Kleifeld O, Glickman MH, Wolf DA and Chang EC. (2009). eIF3 interactome reveals the translasome, a supercomplex linking protein synthesis and degradation machineries. Mol Cell. 36 141-152.
- Onken B, Weiner H, Philips M and Chang EC. (2006). Compartmentalized signaling of Ras in fission yeast. Proc. Natl. Acad. Sci. USA 103:9045-9050.
- Chang EC and Philips RM. (2006). Spatial segregation of Ras signaling—new evidence from fission yeast. Cell Cycle 5:1936-1939.
- Chang EC and Schwechheimer C. (2004). ZOMES III: the interface between signaling and proteolysis. EMBO Rep. 5:1041-1045.
- Yen H-c, Espiritu C and Chang EC. (2003). Rpn5 is a conserved proteasome subunit and required for proper proteasome localization and assembly. J. Biol. Chem. 278:30669-30676.
- Yen H-c and Chang EC. (2003). INT6 — a link between the proteasome and tumorigenesis. Cell Cycle 2:16-18.
- Yen H-c, Gordon C and Chang EC. (2003). Schizosaccharomyces pombe Int6 and Ras homologs regulate cell division and mitotic fidelity via the proteasome. Cell 112:207-217.
- Papadaki P, Pizon V, Onken B and Chang EC. (2002). Two Ras pathways in fission yeast are differentially regulated by two Ras guanine nucleotide exchange factors. Mol. Cell. Biol. 22:4598-4606.
- Yen HS and Chang EC. (2000). Yin6, a fission yeast Int6 homolog, complexes with Moe1 and plays a role in chromosome segregation. Proc. Natl. Acad. Sci. USA. 97:14370-14375.
- Chen CR, Chen J and Chang EC. (2000). A conserved interaction between Moe1 and Mal3 is important for proper spindle formation in Schizosaccharomyces pombe. Mol. Biol. Cell 11:4067-4077.