Acute promyelocytic leukemia (APL;FAB M3) has a balanced t(15;17)(q22;12-21) that rearranges the retinoic acid receptor1 (RAR1) and promyelocytic leukemia (PML) genes. Two features distinguish APL: (1) APL cells express PML/RAR1 resulting from this translocation and (2) all-trans-retinoic acid (RA)treatment of APL induces clinical remissions through successful differentiation therapy. Paradoxically, these responses are linked to expression of PML/RAR1, a dominant-negative transcription factor as our team and others reported. A hallmark of this APL differentiation program is the retinoid proteasome dependent degradation of PML/RAR1. The next challenge in achieving a molecular understanding of retinoid response in APL and other settings is to uncover retinoid target genes that directly regulate differentiation response. Microarray and biochemical analyses were successfully used in the prior funding period to discover the E1-like ubiquitin-activating enzyme, UBE1L, its ubiquitin-related partner, ISG15, and their deconjugase, UBP43, as previously unrecognized retinoid target genes constituting a novel pathway conferring PML/RAR1 degradation. In this A2 revised competing renewal application of NIH RO1-CA062275-14 microarray analyses as well as unique cellular, biochemical and molecular genetic reagents are used to explore the novel retinoid target gene, G0S2, uncovered as one of the most prominent RA induced species in APL and other cells. G0S2 serves an unexpected function as an inhibitor of retinoid response. Through three specific aims this proposal seeks to: (1) establish whether G0S2 is a direct retinoid target gene in APL cells and use proteomic and molecular pharmacology methods to learn if G0S2 phosphorylation directly affects its inhibition;(2) conduct gain and loss of function experiments to reveal how G0S2 regulates retinoid response in APL;and (3) establish in vivo relevancy by retinoid treatment of primary human APL cell cultures and in transgenic APL models. This proposal has implications beyond APL as G0S2 is retinoid induced in hematopoietic and non-hematopoietic tumor cells. Notably, sequence homology searches did not find homology between G0S2 and other species in the human database. Molecular pharmacologic approaches are used to achieve these aims, with unique biochemical, cellular, molecular genetic and transgenic models to probe comprehensively G0S2 function. This revised NIH R0-1 renewal application seeks to elucidate the precise role of G0S2 in RA differentiation response in APL. These findings are relevant to retinoid therapy of other human malignancies.
All-trans-retinoic acid induces clinical remissions by causing differentiation of acute promyelocytic leukemia. A molecular understanding of how retinoic acid confers these effects is needed. This project studies a novel target gene called G0S2 that has been uncovered and regulates retinoic acid response. The mechanistic role of G0S2 in retinoic acid response will be elucidated in this proposal.
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| Uray, Iván P; Dmitrovsky, Ethan; Brown, Powel H (2016) Retinoids and rexinoids in cancer prevention: from laboratory to clinic. Semin Oncol 43:49-64 |
| Liu, Xi; Gold, Kathryn A; Dmitrovsky, Ethan (2015) The Myb-p300 Interaction Is a Novel Molecular Pharmacologic Target. Mol Cancer Ther 14:1273-5 |
| Myung, Ja Hye; Roengvoraphoj, Monic; Tam, Kevin A et al. (2015) Effective capture of circulating tumor cells from a transgenic mouse lung cancer model using dendrimer surfaces immobilized with anti-EGFR. Anal Chem 87:10096-102 |
| Chinyengetere, Fadzai; Sekula, David J; Lu, Yun et al. (2015) Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas. BMC Cancer 15:886 |
| Gui, Jingang; Hu, Zhuting; Tsai, Ching-Yi et al. (2015) MCL1 enhances the survival of CD8+ memory T Cells after viral infection. J Virol 89:2405-14 |
| Wei, Li-Na; Dmintrovsky, Ethan (2015) Retinoids are back. FASEB J 29:1131-5 |
| Ma, Tian; Lopez-Aguiar, Alexandra G N; Li, Aihua et al. (2014) Mice lacking G0S2 are lean and cold-tolerant. Cancer Biol Ther 15:643-50 |
| Busch, Alexander M; Galimberti, Fabrizio; Nehls, Kristen E et al. (2014) All-trans-retinoic acid antagonizes the Hedgehog pathway by inducing patched. Cancer Biol Ther 15:463-72 |
| Aoyama, Kazutoshi; Saha, Asim; Tolar, Jakub et al. (2013) Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. Blood 122:2125-34 |
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