Inhibition of Protein Disulfide Isomerase (PDIA1) Leads to Proteasome-Mediated Degradation of Ubiquitin-like PHD and RING Finger Domain-Containing Protein 1 (UHRF1) and Increased Sensitivity of Glioblastoma Cells to Topoisomerase II Inhibitors.

Glioblastoma (GBM) is the most aggressive brain tumor, and the prognosis remains poor with current available treatments. PDIA1 is considered a promising therapeutic target in GBM. In this study, we demonstrate that targeting PDIA1 results in increased GBM cell death by topoisomerase II (Top-II) inhibitors resulting in proteasome-mediated degradation of the oncogenic protein UHRF1.

Selective repression of the Drosophila cyclin B promoter by retinoblastoma and E2F proteins.

The Cyclin B1 gene encodes a G2/M cyclin that is deregulated in various human cancers, however, the transcriptional regulation of this gene is incompletely understood. The E2F and retinoblastoma family of proteins are involved in this gene's regulation, but there is disagreement on which of the E2F and retinoblastoma proteins interact with the promoter to regulate this gene. Here, we dissect the promoter region of the Drosophila CycB gene, and study the role of Rbf and E2F factors in its regulation.

Diversification of Retinoblastoma Protein Function Associated with Cis and Trans Adaptations.

Retinoblastoma proteins are eukaryotic transcriptional corepressors that play central roles in cell cycle control, among other functions. Although most metazoan genomes encode a single retinoblastoma protein, gene duplications have occurred at least twice: in the vertebrate lineage, leading to Rb, p107, and p130, and in Drosophila, an ancestral Rbf1 gene and a derived Rbf2 gene. Structurally, Rbf1 resembles p107 and p130, and mutation of the gene is lethal.

Genome-Wide Analysis of Drosophila RBf2 Protein Highlights the Diversity of RB Family Targets and Possible Role in Regulation of Ribosome Biosynthesis.

RBf2 is a recently evolved retinoblastoma family member in Drosophila that differs from RBf1, especially in the C-terminus. To investigate whether the unique features of RBf2 contribute to diverse roles in gene regulation, we performed chromatin immunoprecipitation sequencing for both RBf2 and RBf1 in embryos. A previous model for RB-E2F interactions suggested that RBf1 binds dE2F1 or dE2F2, whereas RBf2 is restricted to binding to dE2F2; however, we found that RBf2 targets approximately twice as many genes as RBf1.

Role of Drosophila retinoblastoma protein instability element in cell growth and proliferation.

The RB tumor suppressor, a regulator of the cell cycle, apoptosis, senescence, and differentiation, is frequently mutated in human cancers. We recently described an evolutionarily conserved C-terminal "instability element" (IE) of the Drosophila Rbf1 retinoblastoma protein that regulates its turnover. Misexpression of wild-type or non-phosphorylatable forms of the Rbf1 protein leads to repression of cell cycle genes.

Atrial natriuretic peptide-C receptor-induced attenuation of adenylyl cyclase signaling activates phosphatidylinositol turnover in A10 vascular smooth muscle cells.

Atrial natriuretic peptide (ANP)-C receptor activation has been shown to inhibit adenylyl cyclase (AC) activity as well as to stimulate phospholipase C (PLC) signaling pathways. The present studies were undertaken to investigate whether ANP-C receptor-mediated decreased cAMP levels contribute to the activation of PLC signaling. C-ANP(4-23) [des(Gln(18),Ser(19), Glu(20),Leu(21),Gly(22))ANP(4-23)-NH(2)], a ring-deleted peptide of ANP that interacts specifically with ANP-C receptor, stimulated inositol 1,4,5-tris-phosphate (IP(3)) production (PLC activity) in A10 vascular smooth muscle cells in a concentration- and time-dependent manner.