Cell cycle dysregulation leads to uncontrolled cell proliferation and tumorigenesis. Understanding the molecular mechanisms underlying cell cycle progression can provide clues leading to the identification of key proteins involved in cancer development. In this study, we performed proteomics analysis to identify novel regulators of the cell cycle. We found that potassium channel tetramerization domain containing 12 (KCTD12) was significantly upregulated in M phase compared with S phase. We also found that KCTD12 overexpression not only facilitated the G2/M transition and induced cancer cell proliferation, but also promoted the growth of subcutaneous tumors and Ki-67 proliferation index in mice. Regarding the mechanism underlying these phenomena, cyclin-dependent kinase 1 (CDK1) was identified as an interacting partner of KCTD12 by immunoprecipitation and mass spectrometry analysis, which showed that KCTD12 activated CDK1 and Aurora kinase A (Aurora A) and that the effects of KCTD12 on CDK1 phosphorylation and cell proliferation were abrogated by cell division cycle 25B (CDC25B) silencing. In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects. Furthermore, we analyzed the expression levels of various genes and the correlations between the expression of these genes and survival using tumor tissue microarray and Gene Expression Omnibus (GEO) data sets. The data showed that KCTD12 expression was significantly upregulated in cervical and lung cancers. More importantly, high KCTD12 expression was associated with larger tumor sizes, higher pathological stages and poor patient survival. Collectively, our study demonstrate that KCTD12 binds to CDC25B and activates CDK1 and Aurora A to facilitate the G2/M transition and promote tumorigenesis and that Aurora A phosphorylates KCTD12 at serine 243 to trigger a positive feedback loop, thereby potentiating the effects of KCTD12. Thus, the KCTD12-CDC25B-CDK1-Aurora A axis has important implications for cancer diagnoses and prognoses.
Understanding the microscopic pathophysiological mechanisms underlying acute ischemic stroke (AIS) is vital for facilitating early clinical diagnosis and intervention. In this study, we aimed to quantitatively assess brain iron changes in gray matter (GM) nuclei in patients with AIS via quantitative susceptibility mapping (QSM).
Danggui Buxue Decoction (DBD) is a classic prescription of traditional Chinese medicine that is mainly used for treating clinical anemia for more than 800 years. This prescription has been utilized for nourishing "Qi" and enriching "Blood" for women suffering from menopausal symptoms. Meanwhile, DBD has the role of improving angiogenesis and promoting the neuroprotective functions. Bone marrow-derived endothelial progenitor cells (EPCs) was suboptimal to treat the focal cerebral ischemia (FCI). Thus, it's may be a novel strategy of DBD combined with EPCs transplantation for the FCI.To investigate the mechanistic effects of DBD in combination with EPCs transplantation to improve behavioral function of the FCI and hyperlipidemia.We used rats with hyperlipidemia to develop a FCI model using photo-thrombosis, and treated the DBD in combination with EPCs transplantation. We adopted the Modified Neurological Severity Score to evaluate the neurological deficit, undertook the 2,3,5-triphenyltetrazolium chloride staining to calculate the total infarct volume. We carried out the RT-qPCR, Immunohistochemical analyses, TUNEL, ELISA, and Western blotting to measure the gene and protein levels which related to anti-apoptosis mechanisms and angiogenesis.Administration of DBD in combination with EPCs transplantation was found to improve behavioral function, reducing the infarct volume and decrease the level of total-cholesterole (TC) and low-density lipoprotein-cholesterol (LDL-C). Treatment of DBD plus EPCs increased the mRNA and protein expression of vascular endothelial growth factor A, fibroblastic growth factor-2, and angiopoietin-1 and decreased the apoptosis of endothelial cells by activating the phosphoinositide 3-kinase/protein kinase B/Bcl-xL/Bcl-2 associated death promoter (PI3K/Akt/BAD) pathway and promoting activation of the extracellular signal-regulated kinase (ERK) pathway, which induced angiogenesis directly.Our findings provided that DBD administration combined with EPCs transplantation promoted reconstruction of nervous function. This was achieved by enhancing expression of the growth factors related to anti-apoptosis mechanisms and angiogenesis thanks to regulation of the PI3K/Akt/BAD and ERK signaling pathways, and might be relate to the lowering of TC and LDL-C levels.
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