Transition from cMyc to L-Myc during dendritic cell development coordinated by rising levels of IRF8

During dendritic cell (DC) development, Myc expression in progenitors is replaced by Mycl in mature DCs, but when and how this transition occurs is unknown. We evaluated DC development using reporters for MYC, MYCL, and cell cycle proteins Geminin and CDT1 in wild-type and various mutant mice. For classical type 1 dendritic cells (cDC1s) and plasmacytoid DCs (pDCs), the transition occurred upon their initial specification from common dendritic cell progenitors (CDPs) or common lymphoid progenitors (CLPs), respectively. This transition required high levels of IRF8 and interaction with PU.1, suggesting the use of EICEs within Mycl enhancers. In pDCs, maximal MYCL induction also required the +41kb Irf8 enhancer that controls pDC IRF8 expression. IRF8 also contributed to repression of MYC. While MYC is expressed only in rapidly dividing DC progenitors, MYCL is most highly expressed in DCs that have exited the cell cycle. Thus, IRF8 levels coordinate the Myc-Mycl transition during DC development.

Angiotensin II -induced overexpression of Sirtuin-1 contributes to enhanced expression of Giα proteins and hyperproliferation of vascular smooth muscle cells.

Angiotensin II (Ang II) plays an important role in the regulation of various physiological functions including proliferation, hypertrophy of vascular smooth muscle cells (VSMC) through the overexpression of Giα proteins. Sirtuin1 (Sirt1), a class III histone deacetylase and epigenetic regulator is implicated in a wide range of cellular functions, including migration and growth of VSMC as well as in Ang II-induced hypertension. The present study was undertaken to examine the role of Sirt1 in Ang II-induced overexpression of Giα proteins and hyperproliferation of aortic VSMC. We show that Ang II treatment of VSMC increased the expression of Sirt1 which was attenuated by AT1 and AT2 receptor antagonists, losartan and PD123319 respectively. In addition, knockdown of Sirt1 by siRNA attenuated Ang II-induced overexpression of Giα-2 and Giα-3 proteins, hyperproliferation of VSMC as well as the overexpression of cell cycle proteins, cyclin D1, Cdk4 and phosphorylated retinoblastoma proteins. Furthermore, Ang II-induced increased levels of superoxide anion (O2-) and NADPH oxidase activity and increased phosphorylation of ERK1/2 and AKT that are implicated in enhanced expression of Giα proteins and hyperproliferation of VSMC were also attenuated to control levels by silencing of Sirt1. In addition, depletion of Sirt1 by siRNA also attenuated Ang II-induced enhanced phosphorylation of PDGFR, EGFR and IGFR in VSMC. In summary, our results demonstrate that Ang II increased the expression of Sirt1 which through oxidative stress, growth factor receptor-mediated MAP kinase/AKT signaling pathway enhances the expression of Giα proteins and cell cycle proteins and results in the hyperproliferation of VSMC.

A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes

Successful cell division relies on the timely removal of key cell cycle proteins such as securin. Securin inhibits separase, which cleaves the cohesin rings holding chromosomes together. Securin must be depleted before anaphase to ensure chromosome segregation occurs with anaphase. Here we find that in meiosis I, mouse oocytes contain an excess of securin over separase. We reveal a mechanism that promotes excess securin destruction in prometaphase I. Importantly, this mechanism relies on two phenylalanine residues within the separase-interacting segment (SIS) of securin that are only exposed when securin is not bound to separase. We suggest that these residues facilitate the removal of non-separase-bound securin ahead of metaphase, as inhibiting this period of destruction by mutating both residues causes the majority of oocytes to arrest in meiosis I. We further propose that cellular securin levels exceed the amount an oocyte is capable of removing in metaphase alone, such that the prometaphase destruction mechanism identified here is essential for correct meiotic progression in mouse oocytes.

LncRNAs of Saccharomyces cerevisiae dodge the cell cycle arrest imposed by the ethanol stress

Ethanol impairs many subsystems of Saccharomyces cerevisiae, including the cell cycle. Cyclins and damage checkpoints drive the cell cycle. Two ethanol-responsive lncRNAs in yeast interact with cell cycle proteins, and here we investigated the role of these RNAs on the ethanol-stressed cell cycle. Our network dynamic modeling showed that the higher and lower ethanol tolerant strains undergo a cell cycle arrest during the ethanol stress. However, lower tolerant phenotype arrest in a later phase leading to its faster population rebound after the stress relief. Two lncRNAs can skip the arrests mentioned. The in silico overexpression of lnc9136 of SEY6210 (a lower tolerant strain), and CRISPR-Cas9 partial deletions of this lncRNA, evidenced that the one induces a regular cell cycle even under ethanol stress; this lncRNA binds to Gin4 and Hsl1, driving the Swe1p, Clb1/2, and cell cycle. Moreover, the lnc10883 of BY4742 (a higher tolerant strain) interacts to the Mec1p and represses Bub1p, circumventing the DNA and spindle damage checkpoints keeping a normal cell cycle even under DNA damage. Overall, we present the first evidence of the direct roles of lncRNAs on cell cycle proteins, the dynamics of this system in different ethanol tolerant phenotypes, and a new cell cycle model.

Presence of Human Papillomavirus and Epstein–Barr Virus, but Absence of Merkel Cell Polyomavirus, in Head and Neck Cancer of Non-Smokers and Non-Drinkers

ObjectiveDetermine the presence and prognostic value of human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCPyV), and cell cycle proteins in head and neck squamous cell carcinoma (HNSCC) of non-smokers and non-drinkers (NSND).MethodsClinical characteristics and tumors of 119 NSND with HNSCC were retrospectively collected and analyzed on tissue microarrays. RNAscope in situ hybridization (ISH) was used to screen for the presence of HPV and MCPyV mRNA. Immunohistochemistry was performed for expression of p16 as surrogate marker for HPV, Large T-antigen for MCPyV, and cell cycle proteins p53 and pRb. Positive virus results were confirmed with polymerase chain reaction. For EBV, EBV encoded RNA ISH was performed. Differences in 5-year survival between virus positive and negative tumors were determined by log rank analysis.ResultsAll oropharyngeal tumors (OPSCC) (n = 10) were HPV-positive, in addition to one oral (OSCC) and one nasopharyngeal tumor (NPSCC). The other three NPSCC were EBV-positive. MCPyV was not detected. Patients with HPV or EBV positive tumors did not have a significantly better 5-year disease free or overall survival. Over 70% of virus negative OSCC showed mutant-type p53 expression.ConclusionIn this cohort, all OPSCC and NPSCC showed HPV or EBV presence. Besides one OSCC, all other oral (n = 94), hypopharyngeal (n = 1), and laryngeal (n = 9) tumors were HPV, EBV, and MCPyV negative. This argues against a central role of these viruses in the ethiopathogenesis of tumors outside the oro- and nasopharynx in NSND. So, for the majority of NSND with virus negative OSCC, more research is needed to understand the carcinogenic mechanisms in order to consider targeted therapeutic options.

Necroptosis-inducing iridium(iii) complexes as regulators of cyclin-dependent kinases

Mitochondria-targeted Ir(iii) complexes induce necroptosis and downregulate certain cell cycle proteins to achieve cell cycle arrest and an anti-proliferation effect in drug-resistant lung cancer.

CYCA3;4 Is a Post-Prophase Target of the APC/CCCS52A2 E3-Ligase Controlling Formative Cell Divisions in Arabidopsis

ABSTRACTThe Anaphase Promoting Complex/Cyclosome (APC/C) controls unidirectional progression through the cell cycle by marking key cell cycle proteins for proteasomal turnover. Its activity is temporally regulated by the docking of different activating subunits, known in plants as CDC20 and CCS52. Despite the importance of the APC/C during cell proliferation, the number of identified targets in the plant cell cycle is limited. Here, we used the growth and meristem phenotypes of Arabidopsis CCS52A2-deficient plants in a suppressor mutagenesis screen to identify APC/CCCS52A2 substrates or regulators, resulting in the identification of a mutant cyclin CYCA3;4 allele. CYCA3;4 deficiency partially rescues the early ccs52a2-1 phenotypes, whereas increased CYCA3;4 levels enhances them. Furthermore, whereas CYCA3;4 proteins are promptly broken down after prophase in wild-type plants, they remain present in later stages of mitosis in ccs52a2-1 mutant plants, marking them as APC/CCCS52A2 substrates. Strikingly, CYCA3;4 overexpression results in aberrant root meristem and stomatal divisions, mimicking phenotypes of plants with reduced RBR1 activity. Correspondingly, RBR1 hyperphosphorylation was observed in CYCA3;4-overproducing plants. Our data thus demonstrate that an inability to timely destroy CYCA3;4 attributes to disorganized formative divisions, likely in part caused by the inactivation of RBR1.ONE-SENTENCE SUMMARYTimely post-prophase breakdown of the Arabidopsis cyclin CYCA3;4 by the Anaphase Promoting Complex/Cyclosome is essential for meristem organization and development.