title: The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation.
abstract: Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL), is estimated to affect 10-20 million people worldwide. The transforming ability of HTLV-I has been largely attributed to the viral protein Tax, which modulates the activity of several well-known cell cycle regulators. An important cell cycle regulator, the retinoblastoma (Rb) protein, is often inactivated in many cancers including virally induced cancers. Upon examination of Rb status, we observed a decrease in Rb protein expression in HTLV-1-infected cell lines as well as in ex vivo ATL patient samples. Transient transfection assays indicated that decreased Rb protein levels were Tax dependent. Here, we demonstrate for the first time that Tax directly associates with Rb. This interaction was localized within the B pocket of Rb and the C-terminus of Tax (aa 245-353). Within the C-terminus of Tax, we have identified an LXCXE-like motif, that when mutated resulted in the loss of Tax/Rb interaction. Furthermore, through the use of proteasome inhibitors, such as MG-132, in vivo and proteasome degradation assays in vitro, we found that Tax destabilizes the hypo-phosphorylated (active) form of Rb via the proteasome pathway. Therefore, we propose a model whereby Tax targets Rb to the proteasome by acting as a molecular bridge bringing Rb into contact with the proteasome for degradation.
authors.affiliation: Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, Washington, DC 20037, USA.
authors.forename: Kylene
authors.initials: K
authors.lastname: Kehn
authors.forename: Cynthia de la
authors.initials: Cde L
authors.lastname: Fuente
authors.forename: Katharine
authors.initials: K
authors.lastname: Strouss
authors.forename: Reem
authors.initials: R
authors.lastname: Berro
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: John
authors.initials: J
authors.lastname: Brady
authors.forename: Renaud
authors.initials: R
authors.lastname: Mahieux
authors.forename: Anne
authors.initials: A
authors.lastname: Pumfery
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Bottazzi
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002460:Cell Line; D016356:Gene Products, tax / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D016356:Gene Products, tax; D007976:Leupeptins; D061988:Proteasome Inhibitors; D016160:Retinoblastoma Protein; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde