The Delta-Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism essential for cell fate specification. Mind bomb 1 (Mib1) has been identified as a ubiquitin ligase that promotes the endocytosis of Delta. We now report that mice lacking Mib1 die prior to embryonic day 11.5, with pan-Notch defects in somitogenesis, neurogenesis,vasculogenesis and cardiogenesis. The Mib1–/–embryos exhibit reduced expression of Notch target genes Hes5, Hey1, Hey2 and Heyl, with the loss of N1icd generation. Interestingly, in the Mib1–/–mutants, Dll1 accumulated in the plasma membrane, while it was localized in the cytoplasm near the nucleus in the wild types, indicating that Mib1 is essential for the endocytosis of Notch ligand. In accordance with the pan-Notch defects in Mib1–/– embryos, Mib1 interacts with and regulates all of the Notch ligands, jagged 1 and jagged 2,as well as Dll1, Dll3 and Dll4. Our results show that Mib1 is an essential regulator, but not a potentiator, for generating functional Notch ligands to activate Notch signaling.
Significance By using a series of cell-type–restricted Adeno-Cre vectors, we show that expression of mutant K-Ras in different cell types in mouse lungs can give rise to adenocarcinomas. Moreover, the cell-of-origin appears to be a determining factor in the histopathological characteristics of the resulting tumor. This is most apparent in the early stages of tumor development, whereby different routes of tumor development are taken when either Clara cells or alveolar type 2 cells serve as the initiating cell type. Both the physical site of onset and the marker expression of the early lesions are distinct. Future studies should reveal whether this affects other tumor characteristics, such as the mutation spectrum and response to treatment.
Notch signaling is critical for the stemness of radial glial cells (RGCs) during embryonic neurogenesis. Although Notch-signal-receiving events in RGCs have been well characterized, the signal-sending mechanism by the adjacent cells is poorly understood. Here, we report that conditional inactivation of mind bomb-1 (mib1), an essential component for Notch ligand endocytosis, in mice using the nestin and hGFAP promoters resulted in complete loss of Notch activation, which leads to depletion of RGCs, and premature differentiation into intermediate progenitors (IPs) and finally neurons, which were reverted by the introduction of active Notch1. Interestingly, Mib1 expression is restricted in the migrating IPs and newborn neurons, but not in RGCs. Moreover, sorted Mib1+ IPs and neurons can send the Notch signal to neighboring cells. Our results reveal that not only newborn neurons but also IPs are essential Notch-ligand-presenting cells for maintaining RGC stemness during both symmetric and asymmetric divisions.
Inflammation is a basic pathological mechanism leading to a variety of vascular diseases. The inflammatory reaction involves complex interactions between both circulating and resident leukocytes and the vascular endothelium. In this study, we report evidence for a novel action of TNF-related activation-induced cytokine (TRANCE) as an inflammatory mediator and its underlying signaling mechanism in the vascular wall. TRANCE significantly increased endothelial-leukocyte cell interactions, and this effect was associated with increased expression of the cell adhesion molecules, ICAM-1 and VCAM-1, on the endothelial cells. RT-PCR analysis and promoter assays revealed that expression of these cell adhesion molecules was transcriptionally regulated mainly by activation of the inflammatory transcription factor, NF-κB. TRANCE induced IκB-α phosphorylation and NF-κB activation via a cascade of reactions involving the TNFR-associated factors, phospholipase C, PI3K, and protein kinase C (PKC-α and PKC-ζ). It also led to the production of reactive oxygen species via PKC- and PI3K-dependent activation of NADPH oxidase in the endothelial cells, and antioxidants suppressed the responses to TRANCE. These results demonstrate that TRANCE has an inflammatory action and may play a role in the pathogenesis of inflammation-related diseases.
Although substantial progress has been made in understanding the mechanisms underlying the expression of mtDNA-encoded polypeptides, the regulatory factors involved in mitoribosome-mediated synthesis and simultaneous insertion of mitochondrial oxidative phosphorylation (OXPHOS) polypeptides into the inner membrane of mitochondria are still unclear. In the present study, disruption of the mouse Crif1 gene, which encodes a mitochondrial protein, resulted in a profound deficiency in OXPHOS caused by the disappearance of OXPHOS subunits and complexes in vivo. CRIF1 was associated with large mitoribosomal subunits that were located close to the polypeptide exit tunnel, and the elimination of CRIF1 led to both aberrant synthesis and defective insertion of mtDNA-encoded nascent OXPHOS polypeptides into the inner membrane. CRIF1 interacted with nascent OXPHOS polypeptides and molecular chaperones, e.g., Tid1. Taken together, these results suggest that CRIF1 plays a critical role in the integration of OXPHOS polypeptides into the mitochondrial membrane in mammals.
SummarySmall cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.
Receptor activator of NF-B ligand (RANKL) is a key regulator for mammary gland development during pregnancy. RANKL-deficient mice display impaired development of lobulo-alveolar mammary structures. Similar mammary gland defects have been reported in mice lacking Id2. Here we report that RANKL induces the proliferation of mammary epithelial cells via Id2. RANKL triggers marked nuclear translocation of Id2 in mammary epithelial cells. In vivo studies further demonstrated the defective nuclear translocation of Id2, but the normal expression of cyclin D1, in the mammary epithelial cells of rankl ؊/؊ mice. In vitro studies with nuclear localization sequence-tagged Id2 revealed that the nuclear localization of Id2 itself is critical for the downregulation of p21 promoter activity. Moreover, RANKL stimulation failed to induce cell growth and to downregulate p21 expression in Id2 ؊/؊ mammary epithelial cells. Our results indicate that the inhibitor of helix-loop-helix protein, Id2, is critical to control the proliferation of mammary epithelial cells in response to RANKL stimulation.Mammary gland development mostly occurs postnatally, by the actions of pregnancy hormones, and proceeds in distinct steps. At birth, the mammary anlage consists of a few rudimentary ducts that occupy a small portion of the mammary fat pad. Pronounced ductal outgrowth and branching commences at puberty. At the onset of pregnancy, increased ductal side branching and extensive epithelial cell proliferation occur, resulting in the formation of lobulo-alveolar structures and the differentiation of secretory epithelia (13,14,39). These differentiation steps are essential to form a lactating mammary gland in pregnancy.The TNF family molecule, receptor activator of NF-B ligand (RANKL; also known as OPGL, ODF, and TRANCE), is a key factor for osteoclast differentiation and/or activation and dendritic cell survival (1,20,41,42). RANKL-deficient mice exhibit severe osteopetrosis and tooth eruption failure due to a complete absence of osteoclasts (19). In addition to the regulation of bone remodeling and immune functions, we have previously shown that RANKL plays a critical role in mammary gland development during pregnancy. Mice lacking RANKL or its receptor, RANK, show impaired lobulo-alveolar development during pregnancy, owing to intrinsic defects in both the proliferation and survival of mammary gland epithelial cells (9). These mutant mice also display a complete transcriptional block in the -casein gene. The defect of -casein gene expression in RANKL-null mice is due to the failure of nuclear translocation of CCAAT/enhancer binding protein  (C/EBP) (18). These findings indicate that RANKL and RANK are essential for the development of a lactating mammary gland during pregnancy.In mammary glands, as well as osteoclasts and dendritic cells, RANKL-RANK interactions induce the phosphorylation and/or activation of IB kinase (IKK), a complex composed of IKK␣, IKK, and IKK␥/NEMO (6, 40). This phosphorylation event leads to polyubiquitination and prot...
Lung cancer is a devastating disease and a major therapeutic burden with poor survival rates. It is responsible for 30% of all cancer deaths. Lung cancer is strongly associated with smoking, although some subtypes are also seen in non-smokers. Tumors in the latter group are mostly adenocarcinomas with many carrying mutations in the epidermal growth factor receptor (EGFR). Survival statistics of lung cancer are grim because of its late detection and frequent local and distal metastases. Although DNA sequence information from tumors has revealed a number of frequently occurring mutations, affecting well-known tumor suppressor genes and proto-oncogenes, many of the driver mutations remain ill defined. This is likely due to the involvement of numerous rather infrequently occurring driver mutations that are difficult to distinguish from the very large number of passenger mutations detected in smoking-related lung cancers. Therefore, experimental model systems are indispensable to validate putative driver lesions and to gain insight into their mechanisms of action. Whereas a large fraction of these analyzes can be performed in cell cultures in vitro, in many cases the consequences of the mutations have to be assessed in the context of an intact organism, as this is the context in which the Mendelian selection process of the tumorigenic process took place and the advantages of particular mutations become apparent. Current mouse models for cancer are very suitable for this as they permit mimicking many of the salient features of human tumors. The capacity to swiftly re-engineer complex sets of lesions found in human tumors in mice enables us to assess the contribution of defined combinations of lesions to distinct tumor characteristics such as metastatic behavior and response to therapy. In this review we will describe mouse models of lung cancer and how they are used to better understand the disease and how they are exploited to develop better intervention strategies.
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