Wwtr1 is a widely expressed 14-3-3-binding protein that regulates the activity of several transcription factors involved in development and disease. To elucidate the physiological role of Wwtr1, we generated Wwtr1 ؊/؊ mice by homologous recombination. Surprisingly, although Wwtr1 is known to regulate the activity of Cbfa1, a transcription factor important for bone development, Wwtr1 ؊/؊ mice show only minor skeletal defects. However, Wwtr1 ؊/؊ animals present with renal cysts that lead to end-stage renal disease. Cysts predominantly originate from the dilation of Bowman's spaces and atrophy of glomerular tufts, reminiscent of glomerulocystic kidney disease in humans. A smaller fraction of cysts is derived from tubules, in particular the collecting duct (CD). The corticomedullary accumulation of cysts also shows similarities with nephronophthisis. Cells lining the cysts carry fewer and shorter cilia and the expression of several genes associated with glomerulocystic kidney disease (Ofd1 and Tsc1) or encoding proteins involved in cilia structure and/or function (Tg737, Kif3a, and Dctn5) is decreased in Wwtr1 ؊/؊ kidneys. The loss of cilia integrity and the down-regulation of Dctn5, Kif3a, Pkhd1 and Ofd1 mRNA expression can be recapitulated in a renal CD epithelial cell line, mIMCD3, by reducing Wwtr1 protein levels using siRNA. Thus, Wwtr1 is critical for the integrity of renal cilia and its absence in mice leads to the development of renal cysts, indicating that Wwtr1 may represent a candidate gene for polycystic kidney disease in humans.bone ͉ cilia ͉ cysts ͉ glomerulus ͉ gene expression
Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP-ribosylating enzyme essential for initiating various forms of DNA repair. Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. Through enzyme-dependent chromatin remodeling and enzyme-independent motif recognition, PARP1 also plays important roles in regulating gene expression. Besides presenting current findings on how each process is individually controlled by PARP1, we shall discuss how transcription and DNA repair are so intricately linked that disturbance by PARP1 enzymatic inhibition, enzyme hyperactivation in diseases, and viral replication can favor one function while suppressing the other.
Significance
Killer cell immunoglobulin-like receptors (KIRs) function as key recognition elements in innate immunity. Structural information for inhibitory KIRs 2DL2, 2DL1, and 3DL1 in complex with their respective HLA ligands is available, but such data for activating KIRs are lacking. We report here the successful crystallization and solved structure of the activating KIR2DS2 in complex with HLA-A*11:01. The structure clearly explains the role of Tyr45, which has long puzzled KIR researchers because it differentiates KIR2DS2 from all inhibitory KIRs, and is now shown to bind Thr80 of HLA-A*11:01. Using KIR2DS2 tetramers to bind HLA on live cells, we also provide evidence that peptide sequence can affect KIR–HLA binding. Our data thus resolve a long-standing problem in KIR biology.
p53 tumor suppressor has been widely recognized as the "Guardian of the Genome", reflecting its importance in ensuring the proper functioning of the cell. It is well-known for its function as a transcription factor, capable of mediating both transcriptional activation and repression, which brings about many cellular outcomes such as cell cycle arrest, apoptosis, cellular senescence and DNA repair. The canonical p53 response element (p53RE), which contains two repeats of a decamer motif "RRRCWWGYYY" separated by a spacer of 0 to 13 base-pairs, has been characterized as the regulatory region on the target genes that p53 binds for transcriptional activation. It was thought that p53 generally represses genes that lack this canonical p53RE, presumably through the sequestration of basal transcriptional machinery components or transcription activators. However, characterization of individual genes as well as genome-wide studies utilizing gene expression profiling and chromatin immunoprecipitation uncovered a large number of potential p53-repressed targets. Taken together, there appears to be multiple modes of gene repression by p53 with some being mediated through direct binding of p53 to DNA. The aim of this review is to assess the evidence of p53 mediated transcriptional repression and discuss its role in cellular function.
Highlights d The 12 known HNF4a isoforms are functionally distinct d Monomers of different HNF4a isoforms can dimerize to form functional heterodimers d HNF4a isoform heterodimers are functionally distinct from corresponding homodimers d HNF4a isoform heterodimers are able to activate or repress transcription.
Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related deaths globally. One of the cellular hallmarks of this disease is dysregulation of apoptosis, and a better understanding of this process is important if progress is to be made toward effectively treating HCC. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a RNA-binding protein that is implicated in apoptosis and is upregulated in various cancers, including HCC. In this study, we report new evidence for a crucial role of hnRNP K in suppressing apoptosis in HCC cells. We used the chemotherapeutic agent 5-fluorouracil to induce apoptosis in HCC cell lines and found that hnRNP K was downregulated, independent of both p53 and caspases. Prolonged downregulation of hnRNP K using small interfering RNA (siRNA) significantly decreased cell viability and increased apoptosis in HCC cell lines in a p53-independent manner. Moreover, enhanced tumor necrosis factor-related apoptosis-inducing ligand potency, independent of BH3-interacting domain death agonist (BID) cleavage, was also observed in hnRNP K siRNA-treated cells. Examination of the underlying mechanism revealed that hnRNP K suppresses the activity of various caspases through controlling transcription of the caspase inhibitor XIAP. Taken together, this study establishes that hnRNP K plays an antiapoptotic role in HCC cell lines, independent of p53 status, via the maintenance of high levels of endogenous caspase inhibitors, and also identifies hnRNP K as a possible therapeutic marker for cancer treatment.
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