The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.

The Kaposi's sarcoma-associated herpesvirus (KSHV), the infectious causative agent of Kaposi's sarcoma (KS), encodes a G protein-coupled receptor (vGPCR) implicated in the initiation of KS. Here we demonstrate that Kaposi's sarcomagenesis involves stimulation of tuberin (TSC2) phosphorylation by vGPCR, promoting the activation of mTOR through both direct and paracrine mechanisms. Pharmacologic inhibition of mTOR with rapamycin prevented vGPCR sarcomagenesis, while overactivation of this pathway was sufficient to render endothelial cells oncogenic.

The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi's sarcoma.

The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a G protein-coupled receptor (vGPCR) that has been implicated in the initiation of Kaposi's sarcoma, identifying vGPCR as an attractive target for preventing Kaposi's sarcoma. However, as only a fraction of cells in advanced Kaposi's sarcoma lesions express vGPCR, it is unclear whether this unique viral oncogene contributes to Kaposi's sarcoma progression. We therefore set out to determine whether the few cells that express vGPCR in established tumors represent an appropriate therapeutic target for the treatment of patients with preexisting Kaposi's sarcoma.

Dileucine and YXXL motifs in the cytoplasmic tail of the bovine leukemia virus transmembrane envelope protein affect protein expression on the cell surface.

Several retroviruses downmodulate the cell surface expression of envelope (Env) proteins through peptide sequences located in the cytoplasmic tail of the transmembrane (TM) subunit. We investigated whether cell surface expression of a chimeric protein containing the cytoplasmic domain of the TM protein (CTM) of bovine leukemia virus (BLV) was regulated by two membrane-proximal dileucine motifs or by tyrosine Y487 or Y498 in YXXL motifs. A chimeric protein composed of the extracellular and membrane-spanning portions of human CD8-alpha plus a wild-type (wt) BLV CTM was detectable on the surface of only 40% of the cells in which it was transiently expressed.

Feline immunodeficiency virus Orf-A localizes to the nucleus and induces cell cycle arrest.

Feline immunodeficiency virus (FIV) gene orf-A, also designated orf-2, encodes a 77 amino acid accessory protein reported to be critical for efficient viral replication in vitro and in vivo and previously implicated to encode a Tat protein for FIV. However, recent studies have shown Orf-A to be important in the late steps of the FIV life cycle involved in virion formation and in early steps involved in virus infectivity. The present study reports that expression of a GFP-Orf-A fusion protein in both primate and feline cell lines results in nuclear localization of this FIV accessory protein.

The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia.

Kaposi sarcoma (KS) is a multifocal angioproliferative neoplasm strictly dependent on angiogenic growth factors and cytokines and invariably associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV or HHV8). A G protein-coupled receptor encoded by KSHV (vGPCR) is able to initiate KS-like tumors when targeted to the vascular endothelium of mice. Analogous to human KS, vGPCR sarcomagenesis involves the paracrine secretion of angiogenic growth factors and proinflammatory molecules from vGPCR-expressing cells.

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor.

We have recently engineered an in vivo endothelial cell-specific retroviral gene transfer system and found that a single Kaposi's sarcoma (KS)-associated herpesvirus/human herpesvirus 8 gene encoding a G protein-coupled receptor (vGPCR), is sufficient to induce KS-like tumors in mice. By using this system, we show here that the Akt signaling pathway plays a central role in vGPCR oncogenesis. Indeed, a constitutively active Akt was sufficient to induce benign hemangiomas in mice, whereas heterozyogosity for PTEN (the phosphatase and tension homologue deleted on chromosome 10), modestly enhancing basal Akt activity, dramatically enhanced vGPCR sarcomagenesis.

Feline immunodeficiency virus ORF-Ais required for virus particle formation and virus infectivity.

The orf-A (orf-2) gene of feline immunodeficiency virus (FIV) is a small open reading frame predicted to encode a 77-amino-acid protein that contains putative domains similar to those of the ungulate lentiviral Tat protein. Orf-A is reported to be critical for efficient viral replication in vitro and in vivo. A series of FIV-pPPR-derived proviruses with in-frame deletions and point mutations within orf-A were constructed and tested for replication in feline lymphoid cells.

Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes.

The Kaposi's sarcoma herpesvirus (KSHV) has been identified as the etiologic agent of Kaposi's sarcoma (KS), but initial events leading to KS development remain unclear. Characterization of the KSHV genome reveals the presence of numerous potential oncogenes. To address their contribution to the initiation of the endothelial cell-derived KS tumor, we developed a novel transgenic mouse that enabled endothelial cell-specific infection in vivo using virus expressing candidate KSHV oncogenes.

Suppression of breast cancer growth and angiogenesis by an antisense oligodeoxynucleotide to p21(Waf1/Cip1).

Under some conditions, p21(Waf1/Cip1) plays an assembly factor role for the cyclins and cyclin-dependent kinases, and recent reports demonstrate that p21 can act as an anti-apoptotic protein. Thus, it is logical to exploit this function of p21 as an anti-cancer target. We have performed a pilot study showing that daily subcutaneous injection of a phosphorothioate antisense p21 oligodeoxynucleotide, which we have previously shown to attenuate p21 levels in vitro, into nude mice who have been implanted with highly metastatic breast cancer cells results in inhibition of tumor growth and angiogenesis.