Juanita C. Sharpe, Ph.D.
Department of Biological Sciences
Cancer arises as a result of the inability of damaged cells to initiate a signaling
cascade that results in the destruction of the cell and clearance from the body.
This process, known as apoptosis, is necessary to prevent reproduction of damaged
cells that leads to cancer. A family of proteins known as the Bcl-2 protein family
regulates apoptosis. The Bcl-2 protein family works to promote cell death through
the interaction of death promoting proteins. Bax, a pro-apoptotic member of this
family, initiates the cell death cascade by releasing cytochrome C. Bax has the ability
to mediate cytochrome c release by working in conjunction with cardiolipin. Previous
studies have shown that the presence of cardiolipin enhances the ability of Bax to
form pores in reconstituted membranes through an, as yet, unknown mechanism. Preliminary
data from our lab has begun to elucidate the mechanism of interaction between Bax
and cardiolipin. In the presence of cardiolipin Bax undergoes a unique conformational
change that facilitates the release of molecules from model membranes. The goals
of the current project are to determine the impact that this conformational change
has on the active and functional conformation of Bax. Our goals are to detail the
structural changes and to correlate these changes with the function of Bax at the
membrane. This will be achieved by studying pore formation and oligomerization of
membrane-associated Bax using fluorescent spectroscopic techniques. We will also
study how regions of Bax contributes to membrane recognition, pore formation and oligomerization
through the use of mutants. The two regions of Bax that are of interest are the BH3
domain, also called the putative cardiolipin binding region, and the c-terminal hydrophobic
domain. Understanding the mechanisms of pore formation and oligomerization as well
as how domains of Bax contribute to the membrane-active conformation will enhance
our understanding of apoptosis and aid in our ability to overcome the barriers that
cancer cells erect to evade apoptosis.
Arnoult D., Bartle LM, Skaletskaya A, Poncet D, Naoulfal Z, Park PU, Sharpe Juanita, Richard J. Youle and Victor S. Goldmacher. Cytomegalovirus cell death supressor
vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at
mitochondria. PNAS (2004) 101:21 7988-7993.
Sharpe JC,Arnoult D, and Youle RJ. Control of mitochondrial permeability by Bcl-2 family members.
BBA (2004) 1644107-113.
Arnoult D, Gaume B, Karobowski M, Sharpe JC, Cecconi F, and Youle RJ. Mitochondrial release of AIF and Endog requires caspase
activation downstream of Bax/Bak-mediated permeabilization. EMBO J., 2003 22:4385-99.
Cecelia M.P. Rodrigues, Susana Sola, Jose J.G. Moura, Juanita C. Sharpe, and Clifford J. Steer. Tauroursodeoxycholic Acid Prevents Bax-induced Membrane
Perturbation and Cytochrome c Release in Isolated Mitochondria. Biochemistry, 2003
Gorka Basanez, Juanita C. Sharpe, J. Galanis, Teresa B. Brandt, J.M. Hardwick, and J. Zimmerberg. Bax type apoptotic
proteins porate pure lipid bilayers trhougha mechanism sensitive to intrinsic monolayer
curvature. J. Biol. Chem., 2002 277(51 ):49360-5.
J.C. Sharpe and E. London Diphtheria Toxin Forms Pores of Different Sizes Depending on Its Concentration
in Membranes: Probable Relationship to Oligomerization. Journal of Membrane Biology
Edgar L Glover, Byeong-Gyu Park and Juanita C. Sharpe, THE MUTAGENESIS AND PURIFICATION OF RECOMBINANT
BAX BH3 REGION MUTANTS, 10th Annual Illinois Louis Stokes Alliance For Minority Participation
(Ls-Amp) Student Research Symposium, Glenview, Illinois, October 12-13, 2007.
Agnes K. Kisai, Nkechiyere Vidal Nwani and Juanita C. Sharpe, OPTIMIZATION OF RECOMBINANT BAX EXPRESSION, 10th Annual Illinois
Louis Stokes Alliance For Minority Participation (Ls-Amp) Student Research Symposium,
Glenview, Illinois, October 12-13, 2007.
Michonne C. Berry and Juanita C. Sharpe, Recombinant Bax Preferentially Binds to SUV Containing Cardiolipin
Resulting in a Conformational Change, 9th Annual Illinois LS-AMP Student Research
Conference, Glenview, Illinois, October 607, 2006.
Edgar Glover and Juanita C. Sharpe, Mutagenesis of Bax Causes Reduction in Cardiolipin Binding,
9th Annual Illinois LS-AMP Student Research Conference, Glenview, Illinois, October
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