Forced homo-oligomerization of RARalpha leads to transformation of primary hematopoietic cells.
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.
Haemato-Oncology Section, The Institute of Cancer Research, 237 Fulham Road, South Kensington, London SW3 6JB, United Kingdom.
Colin
C
Kwok
Bernd B
BB
Zeisig
Shuo
S
Dong
Chi Wai Eric
CW
So
D000818:Animals; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism; D006413:Hematopoietic System / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D008970:Molecular Weight; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha
D001704:Biopolymers; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; D009363:Neoplasm Proteins; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha