Human T-Cell Leukemia Virus Type 1 Tax Activates Caveolin-1 Gene Expression

Caveolae are plasma membrane invaginations that function as regulators of signal transduction. Caveolins are a class of oligomeric structural proteins that are both necessary and sufficient for caveolae formation. Caveolin-1 has been shown to regulate multiple cancer-associated processes including cellular transformation, tumor growth, cell migration and metastasis, cell death and survival, multidrug resistance, and angiogenesis. Adult T-cell leukemia (ATL) is a mature CD4+ T-cell malignancy etiologically associated with human T-cell leukemia virus type 1 (HTLV-1). We examined expression of caveolin-1 and caveolin-2 in HTLV-1-infected T-cell lines and primary ATL cells. These cells expressed high levels of caveolin-1 mRNA compared with uninfected T-cell lines and normal PBMCs. However, caveolin-2 mRNA expression was not restricted to HTLV-1-infected T cells. Immunohistochemical staining of caveolin-1 in ATL lymph nodes and skin lesions showed that primary ATL cells were indeed stained strongly positive for caveolin-1. In vitro infection of a human T-cell line with HTLV-1 induced caveolin-1 mRNA expression. The viral protein Tax transcriptionally activated caveolin-1 gene. Using Tax mutants, we demonstrated that Tax-induced caveolin-1 expression required the NF-kappaB and CREB signaling pathways. TGF-beta is an inhibitor of T-cell proliferation and cytotoxicity. HTLV-1-infected T-cell lines and ATL cells are known to be resistant to TGF-beta-induced growth inhibition. We demonstrated that caveolin-1 is able to suppress TGF-beta signaling at the transcriptional level in T cells. Caveolin-1 colocalized with TGF-beta type I receptor in an HTLV-1-infected T-cell line. Thus, we describe a new function of Tax, as a repressor of TGF-beta signaling through caveolin-1 expression, which may play a critical role in ATL leukemogenesis.