Identification of a functionally impaired positive regulatory domain I binding factor 1 transcription repressor in myeloma cell lines.
B cell differentiation into a plasma cell requires expression of the positive regulatory domain zinc finger protein 1 gene (PRDM1) that encodes the positive regulatory domain I binding factor 1 (PRDI-BF1 or Blimp-1) protein. It represses the transcription of specific target genes, including c-myc, the MHC class II trans-activator, Pax-5, and CD23b. In this study we demonstrate the presence of an alternative protein product of the PRDM1 gene. The new protein, PRDI-BF1 beta, has a disrupted PR domain and lacks the amino-terminal 101 aa of the originally described protein. PRDI-BF1 beta has a dramatic loss of repressive function on multiple target genes, but maintains normal DNA-binding activity, nuclear localization, and association with histone deacetylases and deacetylase activity. Myeloma cell lines express the highest levels of PRDM1 beta mRNA relative to the full-length form, while primary cells and several other cell lines have very low, but detectable, levels of PRDM1 beta. RNA analysis and analysis of the PRDM1 promoters demonstrate that PRDI-BF1 beta is generated from the same gene by alternative transcription initiation using an internal promoter. These newly described features of the PRDM1 gene are highly analogous to the PRDM2 (RIZ) and PRDM3 (MDS1-EVI1) genes, in which each express a truncated protein missing the PR domain. The expression of each of the truncated proteins is elevated in cancerous cells and may play an important role in the disease.
Györy
Ildikó
I
H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL 33612, USA.
Fejér
György
G
Ghosh
Nilanjan
N
Seto
Ed
E
Wright
Kenneth L
KL
D017398:Alternative Splicing; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D010954:Plasmacytoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry; D012097:Repressor Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism / Q000502:physiology*; D024363:Transcription Initiation Site; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D006655:Histone Deacetylases