Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

The Department of Cancer Biology46Dept. website:http://www.lerner.ccf.org/cancerbio/Continued from Page 45In fact, Dr Colmenares and colleagues havefound that human SKI is located at distal 1p36.3and is deleted in all the individuals tested whohave this syndrome. Thus, SKI may contribute tosome phenotypes common in the 1p36 deletionsyndrome, particularly to facial clefting. Ski isalso implicated in regulation of the transcriptionfactor Glioblastoma-3 (Gli3). Dr. Colmenaresand collaborators from Japan reported that Skibinds to Gli3 and recruits the histone deacetylasecomplex (Genes & Development 2002;16:2843-8).A Ski mutation enhanced the digit abnormalitiescaused by the Gli3 gene mutation. Thus, Ski playsan important role in pattern formation byregulating the Gli3 activity.Dr. Alex Almasan’s laboratory hasestablished a critical role for the inactivation ofcyclin E/Cdk2 by caspase-mediated cleavageduring apoptosis (Mol. Cell. Biol. 2002;22:2398-409). Cyclin E/Cdk2 is a critical regulator ofcell-cycle progression from G(1) to S in mammaliancells and has an established role in oncogenesis.This proapoptotic mechanism can beinduced by gene-toxic agents such as ionizingradiation in hematopoietic tumor cell lines and isaccompanied by the expression of a novel p18-cyclin E. Caspase-mediated cyclin E cleavageeliminated interaction with Cdk2 and inactivatedthe associated kinase activity. Apoptosis andgeneration of p18-cyclin E were significantlyinhibited by overexpressing the cleavage-resistantcyclin E mutant, indicating a functional role forcaspase-dependent proteolysis of cyclin E inapoptosis of hematopoietic tumor cells.The laboratory of Dr. Sipra Banerjee isuncovering the role of DNA polymerase beta(polβ) in cancer development. She has describedspecific deletions of DNA polβ in differentcancers and has found that the mutant form ofthe enzyme (polβ∆) forms a dominant-negativecomplex in DNA repair. The defective enzymemay facilitate accumulation of mutations inresponse to environmental stimuli, leading to theexpression of a mutator phenotype in differenttumors (Gene Expression 2002;10:115-23).Infection, inflammation and cancer areintimately linked. The laboratory of Dr. JoeDiDonato is studying the role of the IκB kinases(IKKs) activated in response to differentinflammatory stimuli. He described new rolesdiscovered for IKKα, in epidermal differentiationand in B-cell maturation (Science STKE 2001 –http:stke.sciencemag.org/). In epidermaldifferentiation, IKKα regulates the productionof a secreted differentiation factor through apathway that is independent of its role inactivation of NF-κB. In B-cell maturation,conventional NF-κB signal-induced activation ofIKKα results in phosphorylation of p100precursor proteins and increased proteolyticprocessing and constitutive NF-κB activation.The laboratory of Dr. Serpil Erzurum isstudying the role of antioxidants and reactiveoxygen (ROS) and nitrogen species (RNS) in thepathogenesis of lung diseases. The lungs are wellequipped with antioxidant defenses, andaugmentation of these defenses through genetherapy is being studied as a means of preventingcell injury to patients in whom these defenses arecompromised by diseases such as cancer. Thislaboratory has shown that chronically hypoxichuman populations resident at high altitudes inTibet and Bolivia have very high levels of exhalednitric oxide (NO). This fact likely explains thegreater vasodilation and blood flow in theseindividuals (Nature 2001;414:411-2). ROS areimportant in the initiation and promotion of cellsto neoplastic growth; exposure to cigarettesmoke, the primary risk factor in lung cancerdevelopment, leads to high levels of ROS withinthe human airway. Dr Erzurum’s group hasshown that alterations in antioxidant activities,attributable to increased manganese SOD anddecreased catalase protein, and in mRNAexpression occur in lung tumors (Cancer Res.2001;61:8578-85). Since parallel changes inantioxidant activities, protein, and mRNAexpression were noted in lung carcinoma cell linesexposed to proinflammatory cytokines, such astumor necrosis factor-alpha (TNF-α), interleukin(IL)-1beta (IL-1β), and IFN-gamma (IFN-γ),inflammation in the lung may create an intracellularenvironment favorable to DNA damage andthe promotion of cancer.Dr. Jaharul Haque has investigatedaberrant cytokine signaling in malignant gliomas.His laboratory has shown that glioblastomamultiforme (GBM) cells fail to support Jak-Statsignaling in response to both IL-4 and IL-13. Thisfact is in part due to the expression of IL-13Rα2,which acts as a decoy receptor for IL-13. Themechanism of inhibition was mediated via aphysical interaction between the intracellulardomain of IL-13 Rα2 and the cytoplasmicdomain of the IL-4Rα chain (Cancer Res.2002;62:1103-9). The Haque group, in collaborationwith Dr. Michael Vogelbaum (CCF’s BrainTumor Institute), has recently reported that GBMtumors and cell lines contain high levels ofconstitutively activated Stat3 compared withnormal human astrocytes, white matter, andnormal tissue adjacent to tumor. The persistentactivation of Stat3 is, in part, attributable to anautocrine action of IL-6. This activation can beinhibited by the Jak inhibitor AG490 or expressionof a dominant-negative mutant Stat3Continued on Page 47