CircLARP4 Suppresses Cell Proliferation, Invasion and Glycolysis and Promotes Apoptosis in Non-Small Cell Lung Cancer by Targeting miR-135b.

Background: CircLARP4 is reported to act as a tumor suppressor in some cancers. However, the detailed roles and molecular basis of circLARP4 in non-small cell lung cancer (NSCLC) tumorigenesis are still unclear. The aim of the study is to explore the potential roles and molecular basis of circLARP4 in NSCLC tumorigenesis.

Msi2 plays a carcinogenic role in esophageal squamous cell carcinoma via regulation of the Wnt/β-catenin and Hedgehog signaling pathways.

Msi2 has been widely reported to be upregulated and strongly associated with fast progress and poor prognosis in many cancers. However, the expression and role of Msi2 in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, we found that Msi2 was upregulated in ESCC clinical samples, and was significantly associated with tumor size, differentiation status, and lymph node metastasis in ESCC patients.

DDX23-Linc00630-HDAC1 axis activates the Notch pathway to promote metastasis.

Emerging studies demonstrated the roles of long non-coding RNAs (LncRNAs) are being implicated in the progression of many cancers. Here we report the discovery of a critical role for the linc00630 in the development of Non-Small-Cell Lung Cancers (NSCLCs). Screening from the microarray of six paired NSCLCs and adjacent non-tumor tissues, linc00630 showed a significantly higher RNA levels in NSCLCs.

Pen-2 is dispensable for endoproteolysis of presenilin 1, and nicastrin-Aph subcomplex is important for both γ-secretase assembly and substrate recruitment.

γ-secretase is a protease complex with at least four components: presenilin, nicastrin (NCT), anterior pharynx-defective 1 (Aph-1), and presenilin enhancer 2 (Pen-2). In this study, using knockout cell lines and small interfering RNA technology, our data demonstrated that the disappeared presenilin 1 C-terminal fragment (PS1C) caused by knockdown of pen-2 or knockout of NCT or Aph-1 was recovered by the addition of proteasome inhibitors, indicating that Pen-2, as well as NCT and Aph-1α, is dispensable for presenilin endoproteolysis. Our data also demonstrate that the formation of the nicastrin-Aph-1 subcomplex plays not only an important role in γ-secretase complex assembly but also in recruiting substrate C-terminal fragment of amyloid precursor protein generated by β-cleavage.

Death receptor 6 induces apoptosis not through type I or type II pathways, but via a unique mitochondria-dependent pathway by interacting with Bax protein.

Cells undergo apoptosis through two major pathways, the extrinsic pathway (death receptor pathway) and the intrinsic pathway (the mitochondrial pathway). These two pathways can be linked by caspase-8-activated truncated Bid formation. Very recently, death receptor 6 (DR6) was shown to be involved in the neurodegeneration observed in Alzheimer disease.

Residues at P2-P1 positions of epsilon- and zeta-cleavage sites are important in formation of beta-amyloid peptide.

Most of the Alzheimer's disease (AD)-linked mutations in amyloid precursor protein (APP), which cause abnormal production of beta-amyloid (Abeta), are localized at the major beta-secretase-and gamma-secretase cleavage sites. In this study, using an APP-knockout mouse neuronal cell line, our data demonstrated that at the P2-P1 positions of the epsilon-cleavage site at Abeta49 and the zeta-cleavage site at Abeta46, aromatic amino acids caused a strong reduction in total Abeta. On the other hand, residues with a long side chain caused a decrease in Abeta(40) and a concomitant increase in Abeta(42) and Abeta(38).

The GxxxG motif in the transmembrane domain of AbetaPP plays an essential role in the interaction of CTF beta with the gamma-secretase complex and the formation of amyloid-beta.

Gamma-secretase-mediated processing of the amyloid-beta protein precursor (AbetaPP) is a crucial step in the formation of the amyloid-beta peptide (Abeta), but little is known about how the substrate AbetaPP interacts with the gamma-secretase complex. To understand the molecular events involved in gamma-secretase-mediated AbetaPP processing and Abeta formation, in the present study we determined the role of a well conserved GxxxG motif in the transmembrane domain of AbetaPP. Our data clearly demonstrate that substitution of aspartic acid for the key glycine residues in the GxxxG motif almost completely abolished the formation of Abeta.

Effects of gamma-secretase cleavage-region mutations on APP processing and Abeta formation: interpretation with sequential cleavage and alpha-helical model.

Overwhelming evidence supports the amyloid hypothesis of Alzheimer's disease that stipulates that the relative level of the 42 amino acid beta-amyloid peptide (Abeta(42)) in relationship to Abeta(40) is critical to the pathogenesis of the disease. While it is clear that the multi-subunit gamma secretase is responsible for cleavage of the amyloid precursor protein (APP) into Abeta(42) and Abeta(40), the exact molecular mechanisms regulating the production of the various Abeta species remain elusive. To elucidate the underlying mechanisms, we replaced individual amino acid residues from positions 43 to 52 of Abeta with phenylalanine to examine the effects on the production of Abeta(40) and Abeta(42).

Both the N-terminal fragment and the protein-protein interaction domain (PDZ domain) are required for the pro-apoptotic activity of presenilin-associated protein PSAP.

Presenilin-associated protein (PSAP) was originally identified as a PS1-associated, PDZ domain protein. In a subsequent study, PSAP was found to be a mitochondrial apoptotic molecule. In this study, we cloned the PSAP gene and found that it is composed of 12 exons and localizes on chromosome 6.

The same gamma-secretase accounts for the multiple intramembrane cleavages of APP.

It has been hypothesized that different C-terminus of beta-amyloid peptide (Abeta) may be generated by different gamma-secretase activities. Recently, we have identified a new zeta-cleavage site at Abeta46, leading to an important finding that the C-terminus of Abeta is produced by a series of sequential cleavages. This finding prompted us to examine the effects of the known gamma-secretase inhibitors on different steps of the gamma-secretase-mediated sequential cleavages and specifically their effects on the formation and turnover of the intermediate Abeta(46).

Calpain inhibitor MDL28170 modulates Abeta formation by inhibiting the formation of intermediate Abeta46 and protecting Abeta from degradation.

The observations that three major cleavages within the transmembrane domain of APP, namely, the gamma-cleavage, -cleavage, and the newly identified zeta-cleavage, are involved in the generation of secreted Abeta40 and Abeta42 prompted us to determine how the calpain inhibitor III MDL 28170 influences these three cleavages and Abeta formation. With the use of a cell culture system, our data demonstrate that 1) at either high concentrations, or at a low range of concentrations, at early time points, MDL 28170 inhibits the formation of secreted Abeta40 and Abeta42. However, this effect is due to inhibition of the intermediate Abeta46 generation by zeta-cleavage and not due to direct inhibition of the gamma-cleavage that produces Abeta40/42 from Abeta46; 2) at low range of concentrations and at late time points, MDL 28170 causes an increase in secreted Abeta40/42 that likely results from inhibition of degradation of both the initial substrate, CTFbeta, and the final product, Abeta40/42, of gamma-secretase.

gamma-Cleavage is dependent on zeta-cleavage during the proteolytic processing of amyloid precursor protein within its transmembrane domain.

beta-Amyloid precursor protein apparently undergoes at least three major cleavages, gamma-, epsilon-, and the newly identified zeta-cleavage, within its transmembrane domain to produce secreted beta-amyloid protein (Abeta). However, the roles of epsilon- and zeta-cleavages in the formation of secreted Abeta and the relationship among these three cleavages, namely epsilon-, zeta-, and gamma-cleavages, remain elusive. We investigated these issues by attempting to determine the formation and turnover of the intermediate products generated by these cleavages, in the presence or absence of known gamma-secretase inhibitors.

Identification of a new presenilin-dependent zeta-cleavage site within the transmembrane domain of amyloid precursor protein.

Gamma-secretase cleavage of beta-amyloid precursor protein (APP) is crucial in the pathogenesis of Alzheimer disease, because it is the decisive step in the formation of the C terminus of beta-amyloid protein (Abeta). To better understand the molecular events involved in gamma-secretase cleavage of APP, in this study we report the identification of a new intracellular long Abeta species containing residues 1-46 (Abeta46), which led to the identification of a novel zeta-cleavage site between the known gamma- and epsilon-cleavage sites within the transmembrane domain of APP. Our data clearly demonstrate that the new zeta-cleavage is a presenilin-dependent event.