Forced homo-oligomerization of RARalpha leads to transformation of primary hematopoietic cells - PubMed (original) (raw)
Forced homo-oligomerization of RARalpha leads to transformation of primary hematopoietic cells
Colin Kwok et al. Cancer Cell. 2006 Feb.
Free article
Abstract
Almost 100% of APL patients carry chimeric transcripts encoding truncated RARalpha fused to homo-oligomerization domains from partner proteins. To gain further insights into the cellular transformation mechanisms mediated by RARalpha fusion proteins, thorough structure/function analyses have been performed and identified the POZ homo-oligomerization domain as the minimal transformation domain that is necessary and sufficient for PLZF-RARalpha-mediated in vitro transformation of primary hematopoietic cells. A transformation-incompetent PLZF-RARalpha mutant defective in homo-oligomerization but not corepressor interaction could be rescued by synthetic FKBP-oligomerization domains. Furthermore, an artificial FKBP-RARalpha construct not only mimicked various biochemical properties of bona fide RARalpha fusion proteins but also mediated an ATRA-dependent transformation. Taken together, these findings endorse an oligomerization-dependent mechanism for RARalpha-mediated transformation and suggest a potential avenue for molecular therapy.
Comment in
Similar articles
- The integrity of the charged pocket in the BTB/POZ domain is essential for the phenotype induced by the leukemia-associated t(11;17) fusion protein PLZF/RARalpha.
Puccetti E, Zheng X, Brambilla D, Seshire A, Beissert T, Boehrer S, Nürnberger H, Hoelzer D, Ottmann OG, Nervi C, Ruthardt M. Puccetti E, et al. Cancer Res. 2005 Jul 15;65(14):6080-8. doi: 10.1158/0008-5472.CAN-04-3631. Cancer Res. 2005. PMID: 16024608 - The Stat5-RARalpha fusion protein represses transcription and differentiation through interaction with a corepressor complex.
Maurer AB, Wichmann C, Gross A, Kunkel H, Heinzel T, Ruthardt M, Groner B, Grez M. Maurer AB, et al. Blood. 2002 Apr 15;99(8):2647-52. doi: 10.1182/blood.v99.8.2647. Blood. 2002. PMID: 11929749 - Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein.
Jansen JH, Löwenberg B. Jansen JH, et al. Semin Hematol. 2001 Jan;38(1):37-41. doi: 10.1016/s0037-1963(01)90004-6. Semin Hematol. 2001. PMID: 11172538 Review. - Retinoic acid receptor fusion proteins: friend or foe.
Breems-de Ridder MC, Löwenberg B, Jansen JH. Breems-de Ridder MC, et al. Mol Cell Endocrinol. 2000 Jul 25;165(1-2):1-6. doi: 10.1016/s0303-7207(00)00255-0. Mol Cell Endocrinol. 2000. PMID: 10940477 Review.
Cited by
- Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC.
Rice KL, Hormaeche I, Doulatov S, Flatow JM, Grimwade D, Mills KI, Leiva M, Ablain J, Ambardekar C, McConnell MJ, Dick JE, Licht JD. Rice KL, et al. Blood. 2009 Dec 24;114(27):5499-511. doi: 10.1182/blood-2009-03-206524. Epub 2009 Oct 23. Blood. 2009. PMID: 19855079 Free PMC article. - FIP1L1/RARA with breakpoint at FIP1L1 intron 13: a variant translocation in acute promyelocytic leukemia.
Menezes J, Acquadro F, Perez-Pons de la Villa C, García-Sánchez F, Álvarez S, Cigudosa JC. Menezes J, et al. Haematologica. 2011 Oct;96(10):1565-6. doi: 10.3324/haematol.2011.047134. Epub 2011 Jul 12. Haematologica. 2011. PMID: 21750086 Free PMC article. No abstract available. - Aberrant corepressor interactions implicated in PML-RAR(alpha) and PLZF-RAR(alpha) leukemogenesis reflect an altered recruitment and release of specific NCoR and SMRT splice variants.
Mengeling BJ, Phan TQ, Goodson ML, Privalsky ML. Mengeling BJ, et al. J Biol Chem. 2011 Feb 11;286(6):4236-47. doi: 10.1074/jbc.M110.200964. Epub 2010 Dec 3. J Biol Chem. 2011. PMID: 21131350 Free PMC article. - Acute Promyelocytic Leukemia in Children: A Model of Precision Medicine and Chemotherapy-Free Therapy.
Gurnari C, Voso MT, Girardi K, Mastronuzzi A, Strocchio L. Gurnari C, et al. Int J Mol Sci. 2021 Jan 11;22(2):642. doi: 10.3390/ijms22020642. Int J Mol Sci. 2021. PMID: 33440683 Free PMC article. Review. - The PML-Interacting Protein DAXX: Histone Loading Gets into the Picture.
Salomoni P. Salomoni P. Front Oncol. 2013 Jun 7;3:152. doi: 10.3389/fonc.2013.00152. eCollection 2013. Front Oncol. 2013. PMID: 23760585 Free PMC article.