The human T-cell leukemia virus type-1 (HTLV-1) infects and transforms CD4+ Th-lymphocytes and is the etiological agent of adult T-cell leukemia/lymphoma (ATL), an aggressive hematological malignancy that is resistant to most anticancer modalities. Importantly, the molecular events that contribute to oncogenic cellular transformation and T-cell leukemogenesis remain to be completely defined. Several nonstructural and regulatory proteins (Tax, Rex, p30II, p13II, p12I, p8I, Hbz) encoded by a conserved 3'nucleotide sequence, known as pX, in the HTLV-1 genome deregulate cellular signaling pathways and promote neoplastic T-cell transformation. While the retroviral transactivator, Tax, is considered to be the major oncoprotein of HTLV-1, the roles of the other pX factors in tumorigenesis and the progression of malignant disease have not been extensively studied. We have made significant progress in this area and provided the first evidence that the HTLV-1 p30II protein interacts with the c-MYC oncoprotein and augments c-MYC-dependent transactivation and oncogenic potential, dependent upon recruitment of the TIP60 acetyltransferase to p30II/c-MYC transcription complexes. A dominant-negative TIP60Q377E/G380E mutant inhibits cooperation between p30II and c-MYC and abrogates oncogenic foci- formation in vitro. The TIP60-interacting domain of p30II has been mapped in biochemical protein- interaction studies to aa residues 99-154, which reside on an exposed surface of the p30II protein. The TIP60 acetyltransferase is a transcriptional cofactor for both c-MYC and the p53 tumor suppressor. Our preliminary data further demonstrate that p30II induces and interacts with p53 and transactivates the G2/M anti-apoptotic gene, 14-3-3s. Surprisingly, wildtype p53 enhances oncogenic transformation induced by p30II/c-MYC. A p53 DNA-binding mutant, p53-R175H, inhibited p30II/c-MYC oncogenic activity. TIP60 acetylates lysine residue K120 of p53 and differentially regulates the expression of cellular growth-arrest/survival and pro-apoptotic signals. As c-myc oncogene activation induces p53- dependent apoptosis, we hypothesize that p30II coordinately regulates p53 survival genes (e.g., 14-3- 3s, p21Waf1/Cip1, p53R2, gadd45, tigar) and c-MYC to prevent c-MYC-induced cell-death and promote aberrant lymphoproliferation in HTLV-1-infected cells. The proposed research will build upon our preliminary studies by addressing the following Specific Aims: (1) to determine how HTLV-1 p30II-TIP60 and p30II-p53 biochemical interactions modulate c-MYC and p53 functions. (2) To determine how p53 enhances the cooperation between p30II and c-MYC to promote oncogenic transformation. Our findings allude to a novel paradigm for the deregulation of c-MYC and p53 by transforming viruses through interactions with the common transcriptional cofactor, TIP60. The proposed studies will advance our fundamental understanding of the roles of oncoproteins and tumor suppressors in viral carcinogenesis.
Many cancer-inducing viruses promote aberrant cellular growth and proliferation through interactions with oncoproteins and tumor suppressors. We have demonstrated that the HTLV-1 p30II protein interacts with a common transcriptional cofactor of c-MYC and p53 and coordinately regulates c-MYC oncogenic activity and p53 anti-apoptotic functions. The proposed research will advance our understanding of the molecular events involved in retroviral carcinogenesis and may elucidate new targets for anticancer therapy. This R15 AREA project will provide excellent cancer research training opportunities for undergraduates and graduate students to better prepare them for future careers in the basic or clinical oncological sciences.
|Romeo, Megan; Hutchison, Tetiana; Malu, Aditi et al. (2018) The human T-cell leukemia virus type-1 p30II protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis. Virology 518:103-115|
|Hutchison, Tetiana; Malu, Aditi; Yapindi, Laçin et al. (2018) The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30II and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma. Virology 520:39-58|
|Romeo, Megan M; Ko, Bookyung; Kim, Janice et al. (2015) Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30(II) accessory protein and the induction of oncogenic cellular transformation by p30(II)/c-MYC. Virology 476:271-88|