Retinoic Acid Receptor Alpha & Acute

Promyelocytic LeukemiaAli Foertsch

April 2, 2007

BIOL 445

Vitamin A & Retinoic Acid (RA)

http://www.nature.com/ng/journal/v31/n1/images/ng877-I1.gif

Structure of Vitamin A

Structure of Retinoic Acid

Retinoic Receptor Alpha (RARα)

• Steroid/thyroid hormone receptor super-family• Found in the nucleus, NOT the plasma membrane• Transcription factor

http://courses.bio.psu.edu/summer2005/biol430/readings/maden_cns.pdf

What Happens Without RARα: Knockout Mice

• RARα (-/-) null mutation : postnatal lethal

Wild-type testes RARα (-/-) testes

http://www.pnas.org/cgi/content/abstract/90/15/7225

What Happens Without RARα: Double Knockout Mice

• RARα (-/-) / RARγ (-/-) : embryonic lethal• RARα1 (-/-) / RARγ (-/-) : postnatal lethal• RARα1 (-/-) / RARβ2 (-/-) : postnatal lethal• RARβ2 (-/-) / RARγ (-/-) : postnatal lethal

Wild-type RARα (-/-)

RARγ (-/-)

Wild-type RARα (-/-)

RARγ (-/-)http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7607067&dopt=Citation

What Happens Without RARα: Knockout Mice

• Vitamin A Deficient Diet (VAD) : lethal

http://images.google.com/imgres?imgurl=http://mark.asci.ncsu.edu/Nutrition/NutritionSlides/04.jpg&imgrefurl=http://mark.asci.ncsu.edu/Nutrition/NutritionSlides/slides.htm&h=450&w=661&sz=52&hl=en&start=10&um=1&tbnid=qckFxr3DXb9PcM:&tbnh=94&tbnw=138&prev=/images%3Fq%3D%2522vitamin%2BA%2522%2Bdeficient%2Bdiet%26svnum%3D10%26um%3D1%26hl%3Den

Acute Promyelocytic Leukemia (APL)

• Cancer of the blood and bone marrow• Accumulation of promyelocytes in circulation• Chromosomal translocation of RARα from 17 to

15

http://images.google.com/imgres?imgurl=http://www.med-ed.virginia.edu/courses/path/innes/images/wcdjpeg/wcd%2520M3%2520x100%2520b.jpeg&imgrefurl=http://www.med-ed.virginia.edu/courses/path/innes/wcd/myeloid1.cfm&h=172&w=250&sz=35&hl=en&start=5&tbnid=GBEnZnSuUioa8M:&tbnh=76&tbnw=111&prev=/images%3Fq%3Dacute%2Bpromyelocytic%2Bleukemia%26gbv%3D2%26ndsp%3D20%26svnum%3D10%26hl%3Den%26sa%3DN

Chromosomal Translocation in APL

• “Hot spots” in the genome for translocation

• Over 50 identified in the last decade

• These give way to specific leukemia types

http://www.meds.com/molmime/leukemia/guide/1660s15.jpg

Acute Promyelocytic Leukemia (APL)

• Treatable with high concentrations of RA• Physiological [RA] = 10-9 -10-8

• Pharmacological [RA] = 10-7 -10-6 ☺

http://images.google.com/imgres?imgurl=http://www.webtie.org/sots/Meetings/Leukemia/02000/transcripts/gilliland/slides/slide14_trans.jpg&imgrefurl=http://www.webtie.org/sots/Meetings/Leukemia/0200/transcripts/gilliland/Transcript.htm&h=226&w=300&sz=12&hl=en&start=7&tbnid=fp2ncnHFuM:&tbnh=87&tbnw=116&prev=/images%3Fq%3DAcute%2Bpromyelocytic%2Bleukemia%26gbv%3D2%26svnum%3D10%26hl%3Den

So where can I get some Vitamin A??

http://www.nutritionhawaii.org/source/foodguide/vitamin.jpg

Any questions about…

RAR!!

http://lazerbrody.typepad.com/photos/uncategorized/mouse.jpg

Sources• Chambon. 1996. A decade of molecular biology of retinoic acid receptors. FASEB 10

(9): 940-55.• Dermime et al. 1993. Occurance of resistance to retinoic acid in the APL cell line NB4

is associated with altered expression of the pml/RARa protein. Blood 82 (5): 1573-1578.

• Early et al. 1996. Transgenic expression of PML/RARa impairs myelopoiesis. PNAS 93 (15): 7900-7904.

• Goranov et al. 2006. Overexpression of RAR[gamma] increases death of SH-SY5Y. Cell Death and Differentiation 13: 676-679.

• Lamour et al. 1996. Analysis of the ligand-binding domain of human retinoic acid receptor alpha. Molecular and Cellular Biology 16 (10): 5386-92.

• Lin et al. 2001. Transcriptional regulation in acute promyelocytic leukemia. Oncogene 20: 7204-7215.

• Lohnes et al. 1994. Function of the RARs during development. Development 120: 2723-2748.

• Lufkin et al. 1993. High postnatal lethality and testis degeneration in retinoic acid receptor alpha in mutant mice. Proc. Natl. Acad. Sci. USA 90: 7225-7229.

• Maden. 2002. Retinoid Signaling in the development of the central nervous system. Nature 3: 843-853.

• Manshouri et al.1997. Downregulation of RARa in mice by antisense transgene leads to a compensatory increase in RARbeta and RARgamma and development of lymphomas. Blood 89 (7): 2507-2515.

• Perlmann. 2002. Retinoid metabolism: a balancing act. Nature 31: 7-8.• Yamaguchi et al.1998. Retardation of skeletal development and cervical abnormalities

in transgenic mice. PNAS 95 (13): 7491-7496.• Yang et al. 2003. Overexpression of dominant negative RARa causes alveolar

abnormality. Endocrinology 144 (7): 3004-3012.