Cancer Biology  Back to Main

Faculty Detail    
Campus Address VH 140 Zip 0019
Phone  (20-5) -579
Other websites

Faculty Appointment(s)
Appointment Type Department Division Rank

Graduate Biomedical Sciences Affiliations
Biochemistry and Structural Biology 
Cancer Biology 
Integrative Biomedical Sciences 
Medical Scientist Training Program 

Biographical Sketch 
Jeffrey B. Smith received a B.S. degree in chemistry and biology from Illinois State University and a Ph.D. in Biochemistry from the University of Colorado School of Medicine. Following postodoctoral studies at Cornell University and the Imperial Cancer Research Fund, he joined the faculty at the University of Alabama at Birmigham and is presently Professor of Pharmacology and Toxicology. His lab is supported by grants from the National Institutes of Health and from the Department of Defense Cancer Research Program. He served on the Pharmacology Study Section of the National Institutes of Health from 1991 to 1996.

Research/Clinical Interest
Integration of Prodeath and Prosurvival Signals by the Ubiquitin Proteasome System (UPS)
Our laboratory is investigating molecular mechanisms that provoke or prevent genetically programmed cell death (apoptosis). Our chief aim is to elucidate specific prodeath or prosurvival functions of the ubiquitin-proteasome system (UPS), which eliminates intracellular proteins in a tightly controlled manner. Ubiquitin is a small (76 amino acid), highly conserved protein that can be covalently attached to another protein or to itself. Linkage of a polyubiquitin chain to a protein tags it for degradation by the proteasome, a self-compartmentalized multicatalytic protease. The proteasome is abundant (1% of total cell protein) in the cytoplasm and the nucleus of mammalian cells. Our lab found that the intracellular levels of key regulatory enzymes, such as protein kinase C and caspases, are exquisitely regulated by UPS. For example, tumor promoting phorbol esters acutely activate protein kinase C and concomitantly induce polyubiquitination and degradation of the kinase via UPS. Caspases are a family of highly specific cysteine proteases, which implement apoptosis by processing a spectrum of intracellular proteins at one or a few aspartyl residues. Caspase processing generally either activates a prodeath function or disables a prosurvival function of the target protein. Caspase processing of the zeta isoform of protein kinase C activates its kinase function and induces its degradation by UPS. Conditional degradation of caspase by UPS raises the threshold for the induction of apoptosis and thereby averts adventitious cell suicide. Drugs that target UPS are under development for treating cancer, neurodegenerative, and inflammatory diseases.

Selected Publications 
Publication PUBMEDID
Lee HW, Smith L, Pettit GR, Smith JB.Bryostatin 1 and phorbol ester down-modulate protein kinase C-alpha and -epsilon via the ubiquitin/proteasome pathway in human fibroblasts.Mol Pharmacol. 1997 Mar;51(3):439-47.  9058599 
Lee HW, Smith L, Pettit GR, Bingham Smith J.Dephosphorylation of activated protein kinase C contributes to downregulation by bryostatin. Am J Physiol. 1996 Jul;271(1 Pt 1):C304-11.  8760059 
Lee HW, Smith L, Pettit GR, Vinitsky A, Smith JB.Ubiquitination of protein kinase C-alpha and degradation by the proteasome. J Biol Chem. 1996 Aug 30;271(35):20973-6.  8702857 
Smith L, Smith JB.Lack of constitutive activity of the free kinase domain of protein kinase C zeta dependence on transphosphorylation of the activation loop. J Biol Chem. 2002 Sep 19 [epub ahead of print]  12244101 
Smith L, Chen L, Reyland ME, DeVries TA, Talanian RV, Omura S, Smith JB.Activation of atypical protein kinase C zeta by caspase processing and degradation by the ubiquitin-proteasome system. J Biol Chem. 2000 Dec 22;275(51):40620-7.  11016947 
Chen L, Smith L, Johnson MR, Wang K, Diasio RB, Smith JB.Activation of protein kinase C induces nuclear translocation of RFX1 and down-regulates c-myc via an intron 1 X box in undifferentiated leukemia HL-60 cells. J Biol Chem. 2000 Oct 13;275(41):32227-33.  10918054