Silvermanreeves5688

8-Oxoguanine DNA glycosylase (OGG1) is the major cellular enzyme required for the excision of 8-oxoguanine DNA base lesions in DNA through the base excision repair (BER) pathway, and therefore plays a major role in suppressing mutagenesis and in controlling genome stability. However, the mechanism of regulation of cellular OGG1 protein, particularly in response to oxidative stress, is unclear. We have purified the major E3 ubiquitin ligase responsible for OGG1 ubiquitylation from human cell extracts, and identify this as E3 ubiquitin-protein ligase NEDD4-like (NEDD4L). We demonstrate that recombinant NEDD4L stimulates ubiquitylation of OGG1 in vitro, particularly on lysine 341, and that NEDD4L and OGG1 interact in U2OS cells. Depletion of NEDD4L in U2OS cells has no impact on the stability and steady-state protein levels of OGG1, however, OGG1 stability is enhanced in response to oxidative stress induced by ionizing radiation. Furthermore, ubiquitylation of OGG1 by NEDD4L in vitro inhibits its DNA glycosylase/lyase activity. As a consequence of prolonged OGG1 stability and increased excision activity in the absence of NEDD4L, cells display increased DNA repair capacity but conversely that this decreases cell survival post-irradiation. This effect can be reproduced following OGG1 overexpression, suggesting that dysregulation of OGG1 increases the formation of lethal intermediate DNA lesions. Our study therefore highlights the importance of balancing OGG1 protein levels and BER capacity in maintaining genome stability.Janus kinase 2 (JAK2) and signal transducers and activators of transcription 5 (STAT5) are involved in the proliferation, differentiation, and survival of mammary gland epithelial cells. Dysregulation of JAK2-STAT5 activity invariably leads to mammary gland developmental defects and/or diseases, including breast cancer. Proper functioning of the JAK2-STAT5 signaling pathway relies on crosstalk with other signaling pathways (synergistically or antagonistically), which leads to normal biological performance. This review highlights recent progress regarding the critical components of the JAK2-STAT5 pathway and its crosstalk with G-protein coupled receptor (GPCR) signaling, PI3K-Akt signaling, growth factors, inflammatory cytokines, hormone receptors, and cell adhesion.Myocardial infarction (MI), the main cause of cardiovascular-related deaths worldwide, has long been a hot topic because of its threat to public health. S100A8/A9 has recently attracted an increasing amount of interest as a crucial alarmin that regulates the pathogenesis of cardiovascular disease after its release from myeloid cells. However, the role of S100A8/A9 in the etiology of MI is not well understood. Here, we elaborate on the critical roles and potential mechanisms of S100A8/A9 driving the pathogenesis of MI. First, cellular source of S100A8/A9 in infarcted heart is discussed. Then we highlight the effect of S100A8/A9 heterodimer in the early inflammatory period and the late reparative period of MI as well as myocardial ischemia/reperfusion (I/R) injury. Moreover, the predictive value of S100A8/A9 for the risk of recurrence of cardiovascular events is elucidated. Therefore, this review focuses on the molecular mechanisms of S100A8/A9 in MI pathogenesis to provide a promising biomarker and therapeutic target for MI.During embryonic development, sequential waves of hematopoiesis give rise to blood-forming cells with diverse lineage potentials and self-renewal properties. This process must accomplish two important yet divergent goals the rapid generation of differentiated blood cells to meet the needs of the developing embryo and the production of a reservoir of hematopoietic stem cells to provide for life-long hematopoiesis in the adult. Vascular beds in distinct anatomical sites of extraembryonic tissues and the embryo proper provide the necessary conditions to support these divergent objectives, suggesting a critical role for specialized vascular niche cells in regulating disparate blood cell fates during development. In this review, we will examine the current understanding of how organ- and stage-specific vascular niche specialization contributes to the development of the hematopoietic system.Drugs targeting the cyclin-dependent kinase 4/6 (CDK4/6)-retinoblastoma 1 (RB1) axis have shown efficacy against multiple solid cancers, but their therapeutic potential in pancreatic cancer remains poorly defined. AZD2171 in vitro A recent report proposed that a "tailored" combination of first-line and second-line CDK4-targeting drugs would hold promise for pancreatic cancer treatment. Indeed, this therapeutic strategy exhibited significantly suppressive effects on pancreatic cancer patient-derived cell lines and tumor tissue in vitro. However, the study neglected immune involvement and the influence of CDK6 and RB1 in CDK4 inhibition-based treatment. Herein, we reveal multiple new facets of the CDK4/6-RB1 axis in pancreatic cancer, highlighting the complexity of this signaling axis for future prognostic and therapeutic targeting.Cumulative evidence collected in recent decades suggests that lysosomal dysfunction contributes to neurodegenerative diseases, especially if amyloid proteins are involved. Among these, alpha-synuclein (aSyn) that progressively accumulates and aggregates in Lewy bodies is undisputedly a main culprit in Parkinson disease (PD) pathogenesis. Lysosomal dysfunction is evident in brains of PD patients, and mutations in lysosomal enzymes are a major risk factor of PD. At first glance, the role of protein-degrading lysosomes in a disease with pathological protein accumulation seems obvious and should guide the development of straightforward and rational therapeutic targets. However, our review demonstrates that the story is more complicated for aSyn. The protein can possess diverse posttranslational modifications, aggregate formations, and truncations, all of which contribute to a growing known set of proteoforms. These interfere directly or indirectly with lysosome function, reducing their own degradation, and thereby accelerating the protein aggregation and disease process. Conversely, unbalanced lysosomal enzymatic processes can produce truncated aSyn proteoforms that may be more toxic and prone to aggregation. This highlights the possibility of enhancing lysosomal function as a treatment for PD, if it can be confirmed that this approach effectively reduces harmful aSyn proteoforms and does not produce novel, toxic proteoforms.