B-Raf-dependent expression of vascular endothelial growth factor-A in Kaposi sarcoma-associated herpesvirus-infected human B cells.
Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) is etiologically linked to Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease. Vascular endothelial growth factor-A (VEGF-A) is one of the essential factors required in KSHV pathogenesis, mainly due to its ability to mediate angiogenesis. In this report we analyzed the relationship between Raf and VEGF-A expression in KSHV-infected hematopoietic cells. All of the KSHV-infected cell lines (derived from PEL) expressed higher levels of B-Raf and VEGF-A when compared with uninfected cells. Inhibition of Raf to mitogen-induced extracellular kinase (MEK) to extracellular signal-related kinase (ERK) signaling, either by the use of MEK inhibitor (PD98059) or by siRNA specific to B-Raf, significantly lowered VEGF-A expression. In addition, B-Raf-induced VEGF-A expression was demonstrated to be sufficient to enhance tubule formation in endothelial cells. Interestingly, we did not observe mutation in the B-Raf gene of the KSHV-infected PEL cell lines. Taken together, we report for the first time the ability of Raf-associated signaling to play a role in the expression of VEGF-A in KSHV-infected hematopoietic cells.
Akula
Shaw M
SM
Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. akulas@mail.ecu.edu
Ford
Patrick W
PW
Whitman
Audy G
AG
Hamden
Khalief E
KE
Bryan
Benjaman A
BA
Cook
Paul P
PP
McCubrey
James A
JA
D001402:B-Lymphocytes / Q000821:virology*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases; D005786:Gene Expression Regulation; D006566:Herpesviridae Infections / Q000378:metabolism* / Q000473:pathology; D019288:Herpesvirus 8, Human; D006801:Humans; D009389:Neovascularization, Pathologic; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases