Contents - College of Medical and Dental Sciences - University of ...
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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK<br />
Pathogenesis Abstract 17<br />
β ARRESTINS REGULATE KSHV GPCR ACTIVITY AND ARE MODULATED BY<br />
CANNABINOIDS<br />
Xuefeng Zhang, Yehoshua Maor, Jerome E. Groopman<br />
Division <strong>of</strong> Experimental Medicine, Beth Israel Deaconess <strong>Medical</strong> Center, Harvard<br />
<strong>Medical</strong> School, Boston, MA 02115 USA<br />
Abstract<br />
Kaposi’s sarcoma (KS) is a frequent neoplasm among immuno-compromised patients<br />
such as those with AIDS <strong>and</strong> after organ transplantation. Among certain populations,<br />
recreational use <strong>of</strong> cannabinoids is common <strong>and</strong> medicinal use <strong>of</strong> cannabinoids is<br />
increasing as well. Cannabinoids bind to CB1 <strong>and</strong> CB2 GPCRs on the endothelial cell<br />
surface. In our previous study, we found that low doses <strong>of</strong> Δ 9 -tetrahydrocannabinol (Δ 9 -<br />
THC), the major psychoactive ingredient <strong>of</strong> marijuana, induced KSHV GPCR expression<br />
<strong>and</strong> endothelial transformation. Using immunoprecipitation <strong>and</strong> confocal microscopy, we<br />
then found that KSHV GPCR was constitutively associated with β arrestins. β arrestins are<br />
key molecules contributing to desensitization <strong>of</strong> GPCRs. We now report that knockdown<br />
<strong>of</strong> β arrestins using RNAi technology increased KSHV GPCR expression. This resulted in<br />
phosphorylation <strong>of</strong> focal adhesion kinase (FAK) <strong>and</strong> inhibition <strong>of</strong> p53 expression. Such<br />
changes in FAK <strong>and</strong> p53 may contribute to endothelial transformation by KSHV GPCR. We<br />
also found that knockdown <strong>of</strong> β arrestins significantly induced NFκB (p65) expression in<br />
KSHV-infected HMVEC. The NFκB pathway has been observed to participate in KSHV<br />
GPCR-induced transformation. Our results indicate that β arrestins may exert inhibitory<br />
effects on KSHV GPCR activity, <strong>and</strong> when KSHV-infected cells are exposed to a strong<br />
GPCR stimulus like cannabinoids, cytosolic arrestins are preferentially recruited to<br />
activated GPCRs like CB1 <strong>and</strong> CB2. This would significantly decrease association <strong>of</strong> KSHV<br />
GPCR with β arrestins, increasing activity <strong>of</strong> KSHV GPCR <strong>and</strong> enhancing KS<br />
transformation.<br />
Presenting author Email: xzhang3@bidmc.harvard.edu<br />
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