retinoic acid receptor alpha
TRANSCRIPT
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RARARetinoic Acid Receptor Alpha
Taylor Beard
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Big Picture• RARA encodes ligand activated transcription factor
RARα protein• RARα promotes transcription of genes involved in
differentiation and proliferation• Activated by Retinoic Acid (RA) ligand and co-
activators• Acts in a dominant negative manner in Acute
Promyelocytic Leukemia (APL) due to an oncogenic translocation mutation
• Translocation fusion protein PML-RARα inhibits differentiation of promyelocytes
• ATRA (All-Trans Retinoic Acid) treatment restores differentiation
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RARA Protein Structure • N-terminal: transcription modulation region
AF-1 & AF-2
• DNA-binding domain (DBD): Zinc fingers
• Hinge region: allows rotation• Ligand binding region (LBD): ligand binding,
dimerization, and transactivation
• C-terminal: function unknown
• Phosphorylation: Ser 369 residue of LBD
Vigue (2010) Atlas of Genetics and Cytogenetics in Oncology and Haematology
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RARα Function• Ligand activated transcription factor– Ligand = Retinoic Acid (RA)
• RAR/RXR heterodimers bind to Retinoic Acid Response Elements (RAREs) in target genes– heterodimer formed via binding of DBD domains– Target genes: differentiation & proliferation
• Absence of RA:– Recruit corepressors NCoR & SMRT– Histone deacetylase activity: ↑ chromatin compaction – transcriptional repression
• Presence of RA:– ligand-induced conformational changes– Dissociate corepressors & recruit co-activators (SRC/p160)– Histone acetyl- & methylation : ↓ chromatin compaction – transcription promotion
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RARα Mechanism of ActionCOREPRESSORS (NCoR, SMRT)
CO-ACTIVATORS (SRC/p160, p300/CBP, CARM-1)+ RA (ligand)
Niederreither & Dolle (2008) Nature 9:541–553
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Focosi (2001)
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RARA Oncogenic Gene Transformation in APL
• t(15;17) PML-RARA fusion gene- Recruits tightly bound corepressors- Physiological doses of RA inadequate for
activation• Dominant-negative inhibitor of RA signaling
pathway
• Inhibits differentiation of promyelocytes
Melnick & Licht JD (1999) Blood. 93:3167–3215
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Oncogenic Activity in
APL
Goal of APL
Treatment
title
(Promyelocyte) (Mature WBC)Pitha-Rowe et al. (2003) Leukemia 17:1723–1730
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PML-RARα Inhibits Differentiation
Figure 1. Expression of PML-RARα inhibits normal expression of differentiation markers in myeloid precursor cell lines.
(Control) (PML-RARα)
Grignani et al. (1993) Cell 74:423–431
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ATRA Restores Differentiation
Figure 2. (below) Northern blot. ATRA treatment increases mRNA expression of differentiation transcription factor PU.1
Figure 3. (above) Western blot. ATRA treatment results in loss of PML-RARA fusion protein expression and induction of PU.1 protein expression.
Mueller et al. (2006) Blood 107:3330–3338
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Acute Promyelocytic Leukemia (APL)
• A type of acute myeloid leukemia - AML M3• Deficiency of mature WBCs and excess of promyelocytes• Incidence
– Rare: 5% of all AML cases– Higher in Italy and the Americas
• Risk factors– No known environmental risk factors– Any age (mean 40-50 yrs); equal in M/F
• Symptoms: the ‘classic triad’– Fatigue– Bruising and bleeding– Infections and weight loss
• Prognosis– 5 year survival rate: 58.5%
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APL Treatment• Substitution Therapy– Stabilize bleeding tendency
• All-Trans-Retinoic Acid (ATRA)– Promotes differentiation via PML-RARα cleavage
and degradation• Chemotherapy– Eliminates existing tumor cells
• Arsenic Trioxide (ATO)– Degrades PML-RARα via a different pathway than
ATRA
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References• Bastien J, Rochette-Egly C. 2004. Nuclear retinoid receptors and the transcription of retinoid-target genes
Gene. Gene 328:1–16.• Focosi D. 2001. Physiology of adult homo sapiens - blood (haematology : plasma, blood cells, and
coagulation) and lymph [Internet]. Available from: http://www.ufrgs.br/imunovet/molecular_immunology/blood.html
• Grignani Francesco, Ferucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, Mencarelli A, Grignani Fausto, Peschle C, Nicholetti I, et al. 1993. The acute promyelocytic leukemia-specific PML-RARα fusion protein inhibits differentiation and promotes survival of myeloid precursor cells Cell. Cell 74:423–431.
• Lingfelder E, Niederwieser D, Platzbecker U, Schlenk RF, Wörmann J. 2012. Acute Promyelocytic Leukemia (APL) [Internet]. (onkopedia, editor.). Available from: https://www.onkopedia-guidelines.info/en/onkopedia/guidelines/acute-promyelocytic-leukemia-apl/@@view/html/index.html#ID0EG
• Melnick A, Licht JD. 1999. Deconstructing a Disease: RARα, Its Fusion Partners, and Their Roles in the Pathogenesis of Acute Promyelocytic Leukemia Blood. Blood 93:3167–3215.
• Mueller BU, Pabst T, Fos J, Fey MF, Asou N, Buergi U, Tenen DG. 2006. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression Blood. Blood 107:3330–3338.
• Niederreither K, Dolle P. 2008. Retinoic acid in development: towards an integrated view Nature Reviews Genetics. Nature 9:541–553.
• Pitha-Rowe I, Petty WJ, Kitaweeran S, Dmitrovsky E. 2003. Retinoid target genes in acute promyelocytic leukemia Leukemia. Leukemia 17:1723–1730.
• Vigue F. 2010. RARA (Retinoic acid receptor, alpha) [Internet]. (Atlas of Genetics and Cytogenetics in Oncology and Haematology, editor.). Available from: http://atlasgeneticsoncology.org/Genes/RARAID46.html