ABSTRACT
We have identified a novel gene, upstream of the cytokine gene cluster region in 5q23-31, residing within one of the most common deleted segments associated with MDS. The novel gene exhibits significant alternative splicing generating at least six splice variants encoding four putative proline-rich protein isoforms, one of which is Golgi-associated. The gene is ubiquitously expressed and conserved among species with the C. elegans homologue being the most interesting, since it resides within an operon with two other genes, phospholipase D and dishevelled, a member of the Wnt pathway, suggesting a functional association. In addition, the novel gene and other key regulatory genes of the region, such IL3, Ril, AF5q31 and TCF-1, were found to be deleted in an atypical CML case, thus underscoring the significance of this subregion in the leukemogenesis process.
Subject(s)
Alternative Splicing , Carrier Proteins/genetics , Chromosomes, Human, Pair 5 , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics , Adaptor Proteins, Signal Transducing , Amino Acid Sequence , Autophagy-Related Protein 8 Family , Base Sequence , Chromosome Deletion , Gene Expression , Humans , Microfilament Proteins , Molecular Sequence DataABSTRACT
We have shown previously that the hepatic control region 1 (HCR-1) enhances the activity of the human apolipoprotein C-II (apoC-II) promoter in HepG2 cells via two hormone response elements (HREs) present in the apoC-II promoter. In the present paper, we report that the HCR-1 selectively mediates the transactivation of the apoC-II promoter by chenodeoxycholic acid (CDCA) and 9- cis -retinoic acid. CDCA, which is a natural ligand of farnesoid X receptor alpha (FXRalpha), increases the steady-state apoC-II mRNA levels in HepG2 cells. This increase in transcription requires the binding of retinoid X receptor alpha (RXRalpha)-FXRalpha heterodimers to a novel inverted repeat with one nucleotide spacing (IR-1) present in the HCR-1. This element also binds hepatocyte nuclear factor 4 and apoA-I regulatory protein-1. Transactivation of the HCR-1/apoC-II promoter cluster by RXRalpha-FXRalpha heterodimers in the presence of CDCA was abolished by mutations either in the IR-1 HRE of the HCR-1 or in the thyroid HRE of the proximal apoC-II promoter, which binds RXRalpha-thyroid hormone receptor beta (T3Rbeta) heterodimers. The same mutations also abolished transactivation of the HCR-1/apoC-II promoter cluster by RXRalpha-T3Rbeta heterodimers in the presence of tri-iodothyronine. The findings establish synergism between nuclear receptors bound to specific HREs of the proximal apoC-II promoter and the HCR-1, and suggest that this synergism mediates the induction of the HCR-1/apoC-II promoter cluster by bile acids and retinoids.