Alternative Splicing of the Human Cyclin D-binding Myb-like Protein (hDMP1) Yields a Truncated Protein Isoform That Alters Macrophage Differentiation Patterns

Abstract

We have cloned two novel, alternatively spliced messages of human cyclin D-binding Myb-like protein (hDMP1). The known, full-length protein has been named hDMP1␣ and the new isoforms, hDMP1␤ and hDMP1␥. The hDMP1␣, -␤, and -␥ splice variants have unique expression patterns in normal hematopoietic cells; hDMP1␤ mRNA transcripts are strongly expressed in quiescent CD34؉ cells and freshly isolated peripheral blood leukocytes, as compared with hDMP1␣. In contrast, activated T-cells and developing myeloid cells, macrophages, and granulocytes express low levels of hDMP1␤ transcripts, and hDMP1␥ is ubiquitously and weakly expressed. Mouse Dmp1 has been shown to activate CD13/aminopeptidase N (APN) and p19 ARF gene expression via binding to canonical DNA recognition sites in the respective promoters. Assessment of CD13/APN promoter responsiveness demonstrated that hDMP1␣ but not hDMP1␤ and -␥, is a transcriptional activator. Furthermore, hDMP1␤ was found to inhibit the CD13/ APN promoter transactivation ability of hDMP1␣. Stable, ectopic expression of hDMP1␤ and, to a lesser extent hDMP1␥, reduced endogenous cell surface levels of CD13/APN in U937 cells. Moreover, stable, ectopic expression of hDMP1␤ altered phorbol 12-myristate 13-acetate-induced terminal differentiation of U937 cells to macrophages and resulted in maintenance of proliferation. These results demonstrate that hDMP1␤ antagonizes hDMP1␣ activity and suggest that cellular functions of hDMP1 may be regulated by cellular hDMP1 isoform levels.

Dmp1 and tumor suppression

“…One copy of the genes at the hDMP1 locus was reportedly deleted in all the tumor cells with chromosome 7q abnormalities regardless of the detailed karyotype, suggesting that one allele loss of hDMP1 could contribute to 7q-malignancies that are refractory to conventional chemotherapy . It has been reported that the hDMP1 locus encodes at least three splicing variants, that is hDMP1a, b and g (Tschan et al, 2003). The full-length hDMP1a corresponds to murine Dmp1, which positively regulates the p19 Arf -p53 pathway (Tschan et al, 2003).…”

Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer

“…The nontargeting vector SHC002 was used as a control. Lentivirus production and transduction of cells was done as described earlier (14). The vectors contain a puromycin resistance gene and stably transduced cell populations were selected for 2 weeks using puromycin at the concentration 1.5 mg/mL.…”

MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma

“…Lentivirus and retrovirus preparation and transduction Lentiviral vectors expressing hsa-miR-29b precursor or a scrambled vector, anti-sense miR-29b (pMIRRZIP-29b-PA-1) or a control scrambled hairpin vector (System Biosciences, Mountain View, CA, USA) as well as c-Myc were prepared and used to transduce lung cancer cells as described (Tschan et al, 2003). ID1 overexpression was performed using retroviral vectors as described (Gautschi et al, 2008).…”