WIP1 deficiency inhibits HTLV-1 Tax oncogenesis: novel therapeutic prospects for treatment of ATL?
- Nicolas Gillet†1, 2,
- Alexandre Carpentier1, 2,
- Pierre-Yves Barez1, 2 and
- Luc Willems1, 2Email author
© Gillet et al.; licensee BioMed Central Ltd. 2012
Received: 16 November 2012
Accepted: 15 December 2012
Published: 21 December 2012
Attenuation of p53 activity appears to be a major step in Human T-lymphotropic virus type 1 (HTLV-1) Tax transformation. However, p53 genomic mutations are late and rather infrequent events in HTLV-1 induced Adult T cell leukemia (ATL). The paper by Zane et al. shows that a mediator of p53 activity, Wild-type p53-induced phosphatase 1 (Wip1), contributes to Tax-induced oncogenesis in a mouse model. Wip1 may therefore be a novel target for therapeutic approaches.
KeywordsHTLV-1 Tax HBZ p53 Wip1 PPM1D MDM2 DNA damage response Genomic stress ATM Chk2
Wild-type p53-induced phosphatase 1
In the paper by Zane et al., the predicted role of p53 was first validated in a transgenic mouse model, confirming previous reports. By crossing Tax-transgenic and p53 knock-out mice, they show that tumor-free survival is significantly shortened in a p53−/− background. The authors next evaluated the role of Wip1 (Wild-type p53-induced phosphatase 1), a regulator of p53. Interestingly, Wip1 deficiency reduces Tax induced tumorigenesis in Wip1−/− and Wip1+/− mice. Consistent with their inhibitory activity, transient expression of Tax and Wip1 reduced p53 transcriptional activity in reporter assays. Although the mechanisms still need to be further characterized, a plausible model is that Tax and Wip1 cooperate in tumorigenesis via p53 inactivation. The paper by Zane et al. thus extends previous observations showing resistance to transformation by other oncogenes such as Ras, Myc, E1A and Erbb2 in PPM1D deficient cells .
Wip1 is a PP2C family serine/threonine phosphatase that inhibits the function of several tumor suppressor pathways, including ATM, CHK2, p38MAPK and p53 . PPM1D (protein phosphatase, Mg2+/Mn2+ dependent, 1D), the gene encoding Wip1, is aberrantly amplified in different types of human primary cancers. Conversely, deletion of PPM1D in mice decreases tumorigenesis. In breast cancers, p53 mutations are frequent, but tumors with PPM1D amplification rarely harbor p53 mutations. One explanation is that Wip1 promotes tumor formation through its ability to inhibit p53 tumor suppressor function directly or indirectly, thus reducing selective pressure for p53 mutations during the progression of cancer.
The paper by Zane et al. is important because it reveals the potential oncogenic role of Wip1 in Tax-mediated oncogenesis in a model of ATL. A series of open questions remain regarding the biological relevance of Wip1 in patients and the mechanisms involved. First, it is currently unknown if gene amplification of PPM1D occur in ATL as observed in other types of cancers. Like p53 deletions [9, 11], PPM1D genomic amplifications usually appear at late stages of tumorigenesis. Alternatively, it is possible that expression and/or activity of Wip1 are increased in the absence of genomic alteration. The PPM1D promoter contains at least two types of transcription binding sites: one for p53 that creates a negative feedback loop (Figure 1) and another for c-Jun . Current data show that Tax, despite its ability to stimulate AP1, does not activate PPM1D expression in reporter assays. Moreover, Wip1 mRNA expression is not increased in Tax-positive cells. This observation needs to be further validated at the protein level using a larger number of HTLV-1 infected cell lines as well as in patients’ samples. Confocal microscopy indicates that Tax and Wip1 colocalize in the nucleus. Further experiments will be required to determine direct or indirect binding between Wip1 and Tax. However, interactomic and proteomic analyzes currently suggest that both proteins do not physically interact (JC Twizere and OJ Semmes, personal communications).
In the context of HTLV-1 associated oncogenesis, it will be interesting to assess the role of other viral oncogenes like HBZ in the Tax/Wip1/p53 interplay. As an inhibitor of AP1 activity, HBZ might interfere with Wip1 expression. Combined crosses between Tax, Wip1, p53 and HBZ transgenic and knock-out mice could address this question. In this context, it is noteworthy that deletion of p14(ARF), a MDM2 modulator (Figure 1), accelerates osteosarcoma formation further supporting the role of p53 regulation in Tax-induced oncogenesis . ARF is a sensor of hyperproliferative signals such as those from the Ras and Myc oncoproteins. In response to oncogenic stress, ARF causes cell-cycle arrest in G1 and G2/M and is associated with increased p53 and p21 expression. ARF mediates cell-cycle arrest by directly binding to MDM2 and sequesters it in the nucleolus. Sequestration of MDM2 stabilizes and activates p53 which then blocks cellular proliferation. Although ARF does not appear to be aberrantly expressed in ATLL cells , acceleration of Tax-induced tumor formation in ARF-deficient mice further supports the central role exerted by p53.
What are the outcomes of these observations in terms of therapy of ATL? First, Tax-repressed p53 function in HTLV-1-transformed cells is druggable and can be restored by treatment with 9-aminoacridine in a setting absent for p53 genomic alterations . Secondly, arsenic trioxide, which has been recently proposed to prevent relapse of ATL lymphoma patients , augments Chk2/p53-mediated apoptosis by inhibiting Wip1 . Thirdly, Wip1 can directly be targeted by specific inhibitors such as compound M (mercury, [4-Aminophenyl] [6-thioguanosinato-N7,S6]), CCT007093 ([2E,5E]-2,5-Bis[2-thienylmethylene]-cyclopentanone) or thioether cyclic phosphopeptide c (MpSIpYVA) . Alternatively, phosphorothioate antisense oligonucleotides targeting PPM1 and specifically disrupting the binding of ATM–Wip1 or CHK2–Wip1 may be instrumental providing that delivery issues are solved.
In summary, the paper by Zane et al. adds a new piece in the complex puzzle of Tax-induced oncogenesis and reveals a potential new mechanism of p53 attenuation during HTLV-1 pathogenesis opening interesting prospects for therapy.
This work was supported by the “Fonds National de la Recherche Scientifique” (FNRS), the Télévie, the Belgian Foundation against Cancer, the Sixth Research Framework Programme of the European Union (project INCA LSHC-CT-2005-018704), the “Neoangio” excellence program and the “Partenariat Public Privé” PPP INCA of the “Direction générale des Technologies, de la Recherche et de l’Energie/DG06” of the Walloon government, the “Action de Recherche Concertée Glyvir” of the “Communauté française de Belgique”, the “Centre anticancéreux près ULg” (CAC), the “Synbiofor” project of GxABT, the “ULg Fonds Spéciaux pour la Recherche”, the “Plan Cancer” of the “Service Public Fédéral,” and the Interuniversity Attraction Poles (IAP) Program BELVIR initiated by the Belgian Science Policy Office. We thank the GIGA technology platforms. NG (postdoctoral researcher), AC (Télévie fellow), PYB (research fellow) and LW (Research Director) are members of the FNRS. We thank KT Jeang for comments and JC Twizere and OJ Semmes for personal communication of unpublished work.
- Boxus M, Willems L: Mechanisms of HTLV-1 persistence and transformation. Br J Cancer. 2009, 101 (9): 1497-1501. 10.1038/sj.bjc.6605345.PubMed CentralView ArticlePubMedGoogle Scholar
- Martin F, Bangham CR, Ciminale V, Lairmore MD, Murphy EL, Switzer WM, Mahieux R: Conference highlights of the 15th international conference on human retrovirology: HTLV and related retroviruses, 4–8 june 2011, leuven, gembloux, Belgium. Retrovirology. 2011, 8: 86-10.1186/1742-4690-8-86.PubMed CentralView ArticlePubMedGoogle Scholar
- Twizere JC, Kruys V, Lefebvre L, Vanderplasschen A, Collete D, Debacq C, Lai WS, Jauniaux JC, Bernstein LR, Semmes OJ, et al: Interaction of retroviral Tax oncoproteins with tristetraprolin and regulation of tumor necrosis factor-alpha expression. J Nat Cancer Institute. 2003, 95 (24): 1846-1859. 10.1093/jnci/djg118.View ArticleGoogle Scholar
- Zhao T, Matsuoka M: HBZ and its roles in HTLV-1 oncogenesis. Front Microbiol. 2012, 3: 247-PubMed CentralView ArticlePubMedGoogle Scholar
- Hagiya K, Yasunaga J, Satou Y, Ohshima K, Matsuoka M: ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells. Retrovirology. 2011, 8: 19-10.1186/1742-4690-8-19.PubMed CentralView ArticlePubMedGoogle Scholar
- Boxus M, Twizere JC, Legros S, Kettmann R, Willems L: Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program. Blood. 2012, 119 (1): 151-160. 10.1182/blood-2011-05-356790.View ArticlePubMedGoogle Scholar
- Boxus M, Willems L: How the DNA damage response determines the fate of HTLV-1 Tax-expressing cells. Retrovirology. 2012, 9: 2-10.1186/1742-4690-9-2.PubMed CentralView ArticlePubMedGoogle Scholar
- Durkin SS, Guo X, Fryrear KA, Mihaylova VT, Gupta SK, Belgnaoui SM, Haoudi A, Kupfer GM, Semmes OJ: HTLV-1 Tax oncoprotein subverts the cellular DNA damage response via binding to DNA-dependent protein kinase. J Biol Chem. 2008, 283 (52): 36311-36320. 10.1074/jbc.M804931200.PubMed CentralView ArticlePubMedGoogle Scholar
- Takemoto S, Trovato R, Cereseto A, Nicot C, Kislyakova T, Casareto L, Waldmann T, Torelli G, Franchini G: p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells. Blood. 2000, 95 (12): 3939-3944.PubMedGoogle Scholar
- Le Guezennec X, Bulavin DV: WIP1 phosphatase at the crossroads of cancer and aging. Trends biochem sci. 2010, 35 (2): 109-114. 10.1016/j.tibs.2009.09.005.View ArticlePubMedGoogle Scholar
- Dequiedt F, Kettmann R, Burny A, Willems L: Mutations in the p53 tumor-suppressor gene are frequently associated with bovine leukemia virus-induced leukemogenesis in cattle but not in sheep. Virology. 1995, 209 (2): 676-683. 10.1006/viro.1995.1303.View ArticlePubMedGoogle Scholar
- Rauch DA, Hurchla MA, Harding JC, Deng H, Shea LK, Eagleton MC, Niewiesk S, Lairmore MD, Piwnica-Worms D, Rosol TJ, et al: The ARF tumor suppressor regulates bone remodeling and osteosarcoma development in mice. PLoS One. 2010, 5 (12): e15755-10.1371/journal.pone.0015755.PubMed CentralView ArticlePubMedGoogle Scholar
- Jung KJ, Dasgupta A, Huang K, Jeong SJ, Pise-Masison C, Gurova KV, Brady JN: Small-molecule inhibitor which reactivates p53 in human T-cell leukemia virus type 1-transformed cells. J Virol. 2008, 82 (17): 8537-8547. 10.1128/JVI.00690-08.PubMed CentralView ArticlePubMedGoogle Scholar
- Bazarbachi A, Suarez F, Fields P, Hermine O: How I treat adult T-cell leukemia/lymphoma. Blood. 2011, 118 (7): 1736-1745. 10.1182/blood-2011-03-345702.View ArticlePubMedGoogle Scholar
- Yoda A, Toyoshima K, Watanabe Y, Onishi N, Hazaka Y, Tsukuda Y, Tsukada J, Kondo T, Tanaka Y, Minami Y: Arsenic trioxide augments Chk2/p53-mediated apoptosis by inhibiting oncogenic Wip1 phosphatase. J Biol Chem. 2008, 283 (27): 18969-18979. 10.1074/jbc.M800560200.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.