Alterations in the cell cycle regulatory genes result in uncontrolled cell proliferation leading to several disease conditions. Cyclin-dependent kinases (CDK) and their regulatory subunit, cyclins, are essential proteins in cell-cycle progression. The activity of CDK is regulated by a series of phosphorylation and dephosphorylation at different amino acid residues. Cell Division Cycle-25 (CDC25) plays an important role in transitions between cell cycle phases by dephosphorylating and activating CDKs. CDC25B and CDC25C play a major role in G2/M progression, whereas CDC25A assists in G1/S transition. Different isomers of CDC25 expressions are upregulated in various clinicopathological situations. Overexpression of CDC25A deregulates G1/S and G2/M events, including the G2 checkpoint. CDC25B has oncogenic properties. Binding to the 14-3-3 proteins regulates the activity and localization of CDC25B. CDC25C is predominantly a nuclear protein in mammalian cells. At the G2/M transition, mitotic activation of CDC25C protein occurs by its dissociation from 14-3-3 proteins along with its phosphorylation at multiple sites within its N-terminal domain. In this article, we critically reviewed the biology of the activation/deactivation of CDC25 by kinases/phosphatases to maintain the level of CDK–cyclin activities and thus the genomic stability, clinical implications due to dysregulation of CDC25 and potential role of CDC25 inhibitors in diseases.

Cardiovascular calcification was originally considered a passive, degenerative process, however with the advance of cellular and molecular biology techniques it is now appreciated that ectopic calcification is an active biological process. Vascular calcification is the most common form of ectopic calcification, and aging as well as specific disease states such as atherosclerosis, diabetes, and genetic mutations, exhibit this pathology. In the vessels and valves, endothelial cells, smooth muscle cells, and fibroblast-like cells contribute to the formation of extracellular calcified nodules. Research suggests that these vascular cells undergo a phenotypic switch whereby they acquire osteoblast-like characteristics, however the mechanisms driving the early aspects of these cell transitions are not fully understood. Osteoblasts are true bone-forming cells and differentiate from their pluripotent precursor, the mesenchymal stem cell (MSC); vascular cells that acquire the ability to calcify share aspects of the transcriptional programs exhibited by MSCs differentiating into osteoblasts. What is unknown is whether a fully-differentiated vascular cell directly acquires the ability to calcify by the upregulation of osteogenic genes or, whether these vascular cells first de-differentiate into an MSC-like state before obtaining a “second hit” that induces them to re-differentiate down an osteogenic lineage. Addressing these questions will enable progress in preventative and regenerative medicine strategies to combat vascular calcification pathologies. In this review, we will summarize what is known about the phenotypic switching of vascular endothelial, smooth muscle, and valvular cells.

Proliferation and migration of smooth muscle cells and the resultant intimal hyperplasia cause coronary artery bypass graft failure. Both internal mammary artery and saphenous vein are the most commonly used bypass conduits. Although an internal mammary artery graft is immune to restenosis, a saphenous vein graft is prone to develop restenosis. We found significantly higher activity of phosphatase and tensin homolog (PTEN) in the smooth muscle cells of the internal mammary artery than in the saphenous vein. In this article, we critically review the pathophysiology of vein-graft failure with detailed discussion of the involvement of various factors, including PTEN, matrix metalloproteinases, and tissue inhibitor of metalloproteinases, in uncontrolled proliferation and migration of smooth muscle cells towards the lumen, and invasion of the graft conduit. We identified potential target sites that could be useful in preventing and (or) reversing unwanted consequences following coronary artery bypass graft using saphenous vein.

Objective: The recessive disease arterial calcification due to deficiency of CD73 (ACDC) presents with extensive nonatherosclerotic medial layer calcification in lower extremity arteries. Lack of CD73 induces a concomitant increase in TNAP (tissue nonspecific alkaline phosphatase; ALPL ), a key enzyme in ectopic mineralization. Our aim was to investigate how loss of CD73 activity leads to increased ALPL expression and calcification in CD73-deficient patients and assess whether this mechanism may apply to peripheral artery disease calcification. Approach and Results: We previously developed a patient-specific disease model using ACDC primary dermal fibroblasts that recapitulates the calcification phenotype in vitro. We found that lack of CD73-mediated adenosine signaling reduced cAMP production and resulted in increased activation of AKT. The AKT/mTOR (mammalian target of rapamycin) axis blocks autophagy and inducing autophagy prevented calcification; however, we did not observe autophagy defects in ACDC cells. In silico analysis identified a putative FOXO1 (forkhead box O1 protein) binding site in the human ALPL promoter. Exogenous AMP induced FOXO1 nuclear localization in ACDC but not in control cells, and this was prevented with a cAMP analogue or activation of A2a/2b adenosine receptors. Inhibiting FOXO1 reduced ALPL expression and TNAP activity and prevented calcification. Mutating the FOXO1 binding site reduced ALPL promoter activation. Importantly, we provide evidence that non-ACDC calcified femoropopliteal arteries exhibit decreased CD73 and increased FOXO1 levels compared with control arteries. Conclusions: These data show that lack of CD73-mediated cAMP signaling promotes expression of the human ALPL gene via a FOXO1-dependent mechanism. Decreased CD73 and increased FOXO1 was also observed in more common peripheral artery disease calcification.

Molecular assessments at the single cell level can accelerate biological research by providing detailed assessments of cellular organization and tissue heterogeneity in both disease and health. The human kidney has complex multi-cellular states with varying functionality, much of which can now be completely harnessed with recent technological advances in tissue proteomics at a near single-cell level. We discuss the foundational steps in the first application of this mass spectrometry (MS) based proteomics method for analysis of subsections of the normal human kidney, as part of the Kidney Precision Medicine Project (KPMP). Using ∼30-40 laser captured micro-dissected kidney cells, we identified more than 2,500 human proteins, with specificity to the proximal tubular (PT; n = 25 proteins) and glomerular (Glom; n = 67 proteins) regions of the kidney and their unique metabolic functions. This pilot study provides the roadmap for application of our near-single-cell proteomics workflow for analysis of other renal micro-compartments, on a larger scale, to unravel perturbations of renal sub-cellular function in the normal kidney as well as different etiologies of acute and chronic kidney disease.