Human T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Its encoded oncoprotein Tax plays the key roles in HTLV-I-mediated cell transformation and pathogenesis. Although the mechanisms by which the HTLV-I Tax deregulates cellular signaling for oncogenesis have been extensively studied, how Tax itself is regulated remains largely unknown. Here we showed that PDZ-LIM domain-containing protein 2 (PDLIM2, SLIM or Mystique) negatively regulated Tax by promoting poly-ubiquitination and proteasomal degradation of Tax, so that to suppress Tax-mediated signaling activation, cell transformation and oncogenesis both in vitro and in animal. To further define the molecular determinant responsible for PDLIM2 mediated Tax suppression, we characterized that a putative รก-helix motif of PDLIM2 at amino acids 236-254 was crucial for the interaction between PDLIM2 and Tax. PDLIM2 with selective disruption of this short helix lost the tumor suppression function and failed in altering Tax subcellular distribution as well as promoting Tax proteasomal degradation. Additionally, the expression of PDLIM2 was down-regulated in HTLV-I-transformed T cells and primary ATL samples, and the re-introduction of PDLIM2 reversed the tumorigenicity of the malignant cells. The evidence indicated that the counterbalance between HTLV-I Tax and PDLIM2 might determine the outcome of HTLV-I infection. Meanwhile, in those HTLV-I-transformed T cells, we found that DNA methyltransferases (DNMT) 1 and 3b but not 3a were over-expressed, suggesting the involvement of DNA methylation in PDLIM2 repression. Consistently, the hypomethylating agent 5-aza-2-deoxycytidine (5-aza-dC) restored PDLIM2 expression and induced death of these malignant cells. Our studies provided important insights into the function of PDLIM2 in HTLV-I leukemogenicity, long latency and cancer heath disparities. Given the efficient antitumor activity with no obvious toxicity of 5-aza-dC, our studies also suggest potential therapeutic approaches for ATL, a disease with poor treatments.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-09012010-165546 |
| Date | 03 September 2010 |
| Creators | Yan, Pengrong |
| Contributors | Paul Robbins, Jing Hu, Thomas Smithgall, Gutian Xiao, Patrick Moore |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-09012010-165546/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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