Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation.
RAR and AML1 transcription factors are found in leukemias as fusion proteins with PML and ETO, respectively. Association of PML-RAR and AML1-ETO with the nuclear corepressor (N-CoR)/histone deacetylase (HDAC) complex is required to block hematopoietic differentiation. We show that PML-RAR and AML1-ETO exist in vivo within high molecular weight (HMW) nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of N-CoR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results show that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation.
Minucci
S
S
European Institute of Oncology, Department of Experimental Oncology, Milan, Italy. sminucci@ieo.it
Maccarana
M
M
Cioce
M
M
De Luca
P
P
Gelmetti
V
V
Segalla
S
S
Di Croce
L
L
Giavara
S
S
Matteucci
C
C
Gobbi
A
A
Bianchini
A
A
Colombo
E
E
Schiavoni
I
I
Badaracco
G
G
Hu
X
X
Lazar
M A
MA
Landsberger
N
N
Nervi
C
C
Pelicci
P G
PG
D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000209:etiology / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C539127:NCOR1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion; D010446:Peptide Fragments; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D006655:Histone Deacetylases