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

Ashlee Moses, Michael A. Jarvis, Camilo Raggo, Yolanda C. Bell, Rebecca Ruhl, B. G Mattias Luukkonen, Diana J. Griffith, Cecily L. Wait, Brian Druker, Michael Heinrich, Jay Nelson, Klaus Frueh

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8383-8399
Number of pages17
JournalJournal of Virology
Volume76
Issue number16
DOIs
StatePublished - 2002
Externally publishedYes

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Human herpesvirus 8
proto-oncogenes
Human Herpesvirus 8
Proto-Oncogenes
Gene Expression Profiling
stem cell factor
endothelial cells
Stem Cell Factor
Kaposi's Sarcoma
Herpesviridae
sarcoma
Up-Regulation
Endothelial Cells
gene expression
Skin
Pharmacology
Proto-Oncogene Proteins c-kit
Receptor Protein-Tyrosine Kinases
cells
Infection

ASJC Scopus subject areas

  • Immunology

Cite this

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. / Moses, Ashlee; Jarvis, Michael A.; Raggo, Camilo; Bell, Yolanda C.; Ruhl, Rebecca; Luukkonen, B. G Mattias; Griffith, Diana J.; Wait, Cecily L.; Druker, Brian; Heinrich, Michael; Nelson, Jay; Frueh, Klaus.

In: Journal of Virology, Vol. 76, No. 16, 2002, p. 8383-8399.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Moses, Ashlee

AU - Jarvis, Michael A.

AU - Raggo, Camilo

AU - Bell, Yolanda C.

AU - Ruhl, Rebecca

AU - Luukkonen, B. G Mattias

AU - Griffith, Diana J.

AU - Wait, Cecily L.

AU - Druker, Brian

AU - Heinrich, Michael

AU - Nelson, Jay

AU - Frueh, Klaus

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