The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation.
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.
Kehn
Kylene
K
Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, Washington, DC 20037, USA.
Fuente
Cynthia de la
Cde L
Strouss
Katharine
K
Berro
Reem
R
Jiang
Hua
H
Brady
John
J
Mahieux
Renaud
R
Pumfery
Anne
A
Bottazzi
Maria Elena
ME
Kashanchi
Fatah
F
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
D016356:Gene Products, tax; D007976:Leupeptins; D061988:Proteasome Inhibitors; D016160:Retinoblastoma Protein; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde