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Regulation of HTLV-I oncoprotein Tax by PDLIM2

Yan, Pengrong (2010) Regulation of HTLV-I oncoprotein Tax by PDLIM2. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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 á-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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairXiao,
Committee MemberHu, Jinghuj3@upmc.eduJIH25
Committee MemberMoore, Patrickpsm9@pitt.eduPSM9
Committee MemberRobbins, Paulprobb@pitt.eduPROBB
Committee MemberSmithgall, Thomastsmithga@pitt.eduTSMITHGA
Date: 3 September 2010
Date Type: Completion
Defense Date: 5 August 2010
Approval Date: 3 September 2010
Submission Date: 1 September 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ATL; HTLV-I; NF-kB; PDLIM2; Tax; tumorigenesis
Other ID:, etd-09012010-165546
Date Deposited: 10 Nov 2011 20:01
Last Modified: 19 Dec 2016 14:37


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