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Gillian
Air
/ Sanjay
Bidichandani / Robert
Broyles Jialing Lin / Hiroyuki Matsumoto / Blaine Mooers / Ann Louise Olson Karla Rodgers / Robert Steinberg / Leon Unger / Paul Weigel / Christopher West |
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Bcl-2 family proteins regulated cell death and its relationship to development and treatment of cancer; Biosynthesis and functional structure of membrane proteins. Programmed cell death (apoptosis) plays an essential role in embryogenesis and adult tissue homeostasis of multicellular organisms by removing unwanted and damaged cells. Impaired regulation of apoptosis is implicated in diseases from cancer to autoimmune disorder to degenerative syndrome. In fact evading apoptosis has been identified as the first of the six critical steps toward carcinogenesis. Two kinds of signals can trigger apoptosis, the death signals received by death receptors on cell surface and the stress signals such as depletion of growth factor and genotypic damages. These apoptotic signals provoke the activation of a set of proteases and nucleases that cleave critical proteins and DNAs to dismantle the cell. Various apoptotic stimuli route through mitochondria to signal the death device. Not surprisingly the decision to launch death program relies primarily on those Bcl-2 family proteins that sooner or later use the mitochondria as their battle field. The Bcl-2 family includes anti-apoptotic Bcl-2, pro-apoptotic Bax and pro-apoptotic BH3 proteins. These proteins share sequence homology in at least one of the four Bcl-2 homology (BH) motifs. Various stress/death signals activate BH3 proteins. This enhances the interactions of BH3 proteins with the mitochondria and other Bcl-2 family proteins. A few active BH3 proteins can directly activate Bax proteins. Active Bax proteins change conformation, insert into the mitochondrial membrane and form oligomers. The Bax oligomers permeabilize the mitochondrial membrane, releasing pro-death proteins that activate caspases and nucleases and triggering apoptosis. Bcl-2 proteins bind active Bax proteins, preventing them from oligomerization in and permeabilization of the mitochondrial membrane. Many BH3 proteins can bind the Bcl-2 proteins, preventing them from interacting and inhibiting Bax proteins. The interactions among Bcl-2 family proteins are thus complex. Which interaction(s) plays a dominant role in the decision-making process during apoptosis induction has always been a hotly debated issue since the discovery of Bcl-2 family. My group is currently addressing the following important questions about the structure and function of Bcl-2 family proteins. How Bcl-2 protects cells, and how BH3 and Bax kill cells? How Bcl-2 inhibits Bax, and how BH3 inhibits Bcl-2? What is the structure of these proteins in healthy or dying cells? What is the structure of these proteins told us about their function during cell death? Can we use the structural information to design drugs that will alter the function of these proteins? Will these drugs be effective in kill cancer cells? We are using a combination of biochemical, biophysical, cell biological and molecular approaches to answer these questions in model systems related to various cancers. We are also interested in setting up collaborations to study Bcl-2 family proteins in other disease-related model systems.
Recent Publications: Leber, B., Lin, J., Andrews, D. (2007) Embedded together: The life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis 12:897-911.
Peng, J., Tan, C., Roberts, G.J., Nikolaeva, O., Zhang, Z., Lapolla, S.M., Primorac, S., Andrews, D.W., and Lin, J. (2006) tBid elicits a conformational alteration in the membrane-bound Bcl-2 such that it inhibits Bax pore formation. J. Biol. Chem. 281:35802-35811.
Leber, B., Lin, J., and Andrews, D.W. Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis, In press.
Tan, C., Dlugosz, P.J., Peng, J., Zhang, Z., Lapolla, S.M., Andrews, D.W., and Lin, J. (2006) Auto-activation of the apoptosis protein Bax increases mitochondrial membrane permeability and is inhibited by Bcl-2. J. Biol. Chem. 281:14764-14775.
Dlugosz, P.J., Billen, L., Annis, M.G., Zhu, W., Zhang, Z., Lin, J., Leber, B., and Andrews, D.W. (2006) Bcl-2 changes conformation to inhibit Bax oligomerization. EMBO J. 25:2287-2296.
Zhang, Z., Lapolla, S.M., Annis, M.G., Truscott, M., Roberts, G.J., Miao, Y., Shao, Y., Tan, C., Peng, J., Johnson, A.E., Zhang, X.C., Andrews, D.W., and Lin, J. (2004) Bcl-2 homodimerization involves two distinct binding surfaces, a topographic arrangement that provides an effective mechanism for Bcl-2 to capture activated Bax. J. Biol. Chem. 279: 43920-43928.
McCormick, P.J., Miao, Y., Shao, Y., Lin, J., and Johnson, A.E. (2003) Cotranslational protein integration into the ER membrane is mediated by the binding of nascent chains to translocon proteins. Mol. Cell, 12: 329-341.
Flanagan JJ, Chen J-C, Miao Y, Shao Y, Lin J, Bock PE, Johnson AE, (2003) SRP binds to ribosome-bound signal sequences with fluorescence-detected subnanomolar affinity that does not diminish as the nascent chain lengthens. J. Biol. Chem. 278: 18628-18637.
Johnson A, Chen J, Flanagan J, Miao Y, Shao Y, Lin J, and Bock P, (2002) Structure, Function and Regulation of Free and Membrane-bound Ribosomes: The View from Their Substrates and Products. Cold Spring Harbor Symposia on Quantitative Biology 66: 531-541.
Lin J, Liang Z, Zhang Z, and Li G, (2001) Membrane topography and topogenesis of prenylated Rab acceptor (PRA1). J. Biol. Chem. 276: 41733-41741.
Xia Z, Zhou Q, Lin J, and Liu Y, (2001) Stable SNARE complex prior to evoked synaptic vesicle fusion revealed by fluorescence resonance energy transfer. J. Biol. Chem. 276: 1766-1771.
Lin J, Liao S, Do H, and Johnson A.E, (1997) Both lumenal and cytosolic gating of the aqueous ER translocon pore are regulated from inside the ribosome during membrane protein integration. Cell 90: 31-41. |
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