Characterization of c-Kit expression and activation in KSHV-infected endothelial cells.
Kaposi's sarcoma (KS) herpesvirus (KSHV) is the etiological agent of several immunodeficiency-linked cancers, including KS. Our previous work showed that the proto-oncogene c-kit is upregulated in KSHV-infected endothelial cells (ECs), as well as in KS lesions. We show here that KSHV-dependent induction of both c-kit mRNA and protein requires the establishment of a latent infection and that this upregulation occurs in primary DMVECs as well as in immortalized DMVECs (eDMVECs). Interestingly, we find that while the lymphatic EC (LEC) subpopulation exhibits KSHV-induced c-Kit upregulation, the blood EC (BEC) subpopulation does not. Despite this upregulation of c-Kit, receptor activation and phosphorylation of downstream effectors such as MAP Kinase Erk 1/2 and GSK-3 still requires the addition of exogenous c-Kit ligand, stem cell factor (SCF). These data indicate that KSHV does not induce constitutive c-Kit signaling, but instead upregulates c-Kit receptor levels, thus allowing infected ECs to respond to endogenous and exogenous SCF. Nonetheless, inhibition of either c-Kit activation or its downstream effectors reverses the characteristic spindle phenotype of infected eDMVECs. Together, these results contribute to our overall understanding of the role that the c-kit proto-oncogene plays in KS pathogenesis.
Douglas
Janet L
JL
Vaccine and Gene Therapy Institute, Oregon Health and Sciences University, 505 NW 185th Ave., Beaverton, OR 97006, USA. dougljan@ohsu.edu
Whitford
Jill G
JG
Moses
Ashlee V
AV
D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*; D019089:Stem Cell Factor / Q000378:metabolism; D017735:Virus Latency
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit