Kaposi's sarcoma-associated herpesvirus-induced upregulation of the c-kit proto-oncogene, as identified by gene expression profiling, is essential for the transformation of endothelial cells.
Kaposi's sarcoma (KS), the most frequent malignancy afflicting AIDS patients, is characterized by spindle cell formation and vascularization. Infection with KS-associated herpesvirus (KSHV) is consistently observed in all forms of KS. Spindle cell formation can be replicated in vitro by infection of dermal microvascular endothelial cells (DMVEC) with KSHV. To study the molecular mechanism of this transformation, we compared RNA expression profiles of KSHV-infected and mock-infected DMVEC. Induction of several proto-oncogenes was observed, particularly the receptor tyrosine kinase c-kit. Consistent with increased c-Kit expression, KHSV-infected DMVEC displayed enhanced proliferation in response to the c-Kit ligand, stem cell factor (SCF). Inhibition of c-Kit activity with either a pharmacological inhibitor of c-Kit (STI 571) or a dominant-negative c-Kit protein reversed SCF-dependent proliferation. Importantly, inhibition of c-Kit signal transduction reversed the KSHV-induced morphological transformation of DMVEC. Furthermore, overexpression studies showed that c-Kit was sufficient to induce spindle cell formation. Together, these data demonstrate an essential role for c-Kit in KS tumorigenesis and reveal a target for pharmacological intervention.
Moses
Ashlee V
AV
Vaccine and Gene Therapy Institute, Portland, Oregon 97201, USA. mosesa@ohsu.edu
Jarvis
Michael A
MA
Raggo
Camilo
C
Bell
Yolanda C
YC
Ruhl
Rebecca
R
Luukkonen
B G Mattias
BG
Griffith
Diana J
DJ
Wait
Cecily L
CL
Druker
Brian J
BJ
Heinrich
Michael C
MC
Nelson
Jay A
JA
Früh
Klaus
K
D001483:Base Sequence; D001549:Benzamides; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D048429:Cell Size; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics; D004247:DNA / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D020869:Gene Expression Profiling; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D000068877:Imatinib Mesylate; D009389:Neovascularization, Pathologic; D010879:Piperazines / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011519:Proto-Oncogenes; D011743:Pyrimidines / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000209:etiology; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology; D015854:Up-Regulation
D001549:Benzamides; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit