Transactivation functions of the tumor-specific HMGA2/LPP fusion protein are augmented by wild-type HMGA2.
The gene encoding the architectural transcription factor HMGA2 is frequently rearranged in several benign tumors of mesenchymal origin. The lipoma preferred partner (LPP) gene is the most frequent translocation partner of HMGA2 in a subgroup of lipomas, which are benign tumors of adipose tissue. In these lipomas, HMGA2/LPP fusion transcripts are expressed, which encode for the three AT-hooks of HMGA2 followed by the two most carboxyl-terminal LIM domains (protein-protein interaction domains) of LPP. Identical fusion transcripts are also expressed in other benign mesenchymal tumors. Previous studies revealed that the LIM domains of LPP have transcriptional activation capacity in GAL4-based luciferase reporter assays. Here, we show that the HMGA2/LPP fusion protein retains the transactivation functions of the LPP LIM domains and thus functions as transcription factor. The HMGA2/LPP fusion protein activates transcription from the well-characterized PRDII element, which is a part of the IFN-beta enhancer and which is known to bind to HMGA2. We also show that HMGA2/LPP activates transcription from the BAT-1 element of the rhodopsin promoter, a HMGA1-binding element. HMGA1 is a closely related family member of HMGA2. Finally, in a number of lipomas, HMGA2/LPP and HMGA2 are coexpressed, and HMGA2 augments the transactivation functions of HMGA2/LPP. These results support the concept that the transactivation functions of the novel HMGA2/LPP transcription factor contribute to lipomagenesis.
Crombez
Koen R M O
KR
Department of Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, Herestraat 49 bus 602, B-3000 Leuven, Belgium.
Vanoirbeek
Els M R
EM
Van de Ven
Wim J M
WJ
Petit
Marleen M R
MM
D020816:Amino Acid Motifs; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D024003:HMGA Proteins / Q000235:genetics / Q000502:physiology*; D025743:HMGA2 Protein / Q000235:genetics / Q000502:physiology*; D006801:Humans; D060588:LIM Domain Proteins; D008067:Lipoma / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D012243:Rhodopsin / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D003598:Cytoskeletal Proteins; D024003:HMGA Proteins; D025743:HMGA2 Protein; C502535:HMGA2-LPP fusion protein, human; D060588:LIM Domain Proteins; C103594:LPP protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012243:Rhodopsin