scholarly journals Essential Role of AKT-1/Protein Kinase Bα in PTEN-Controlled Tumorigenesis

2002 ◽  
Vol 22 (11) ◽  
pp. 3842-3851 ◽  
Author(s):  
Bangyan Stiles ◽  
Valeriya Gilman ◽  
Natalya Khanzenzon ◽  
Ralf Lesche ◽  
Annie Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Survival ◽  
Essential Role ◽  
Es Cells ◽  
Familial Cancer ◽  
Embryonic Stem ◽  
Cellular Processes ◽  
Downstream Effectors

ABSTRACT PTEN is mutated at high frequency in many primary human cancers and several familial cancer predisposition disorders. Activation of AKT is a common event in tumors in which the PTEN gene has been inactivated. We previously showed that deletion of the murine Pten gene in embryonic stem (ES) cells led to increased phosphatidylinositol triphosphate (PIP3) accumulation, enhanced entry into S phase, and better cell survival. Since PIP3 controls multiple signaling molecules, it was not clear to what degree the observed phenotypes were due to deregulated AKT activity. In this study, we mutated Akt-1 in Pten −/− ES cells to directly assess the role of AKT-1 in PTEN-controlled cellular processes, such as cell proliferation, cell survival, and tumorigenesis in nude mice. We showed that AKT-1 is one of the major downstream effectors of PTEN in ES cells and that activation of AKT-1 is required for both the cell survival and cell proliferation phenotypes observed in Pten −/− ES cells. Deletion of Akt-1 partially reverses the aggressive growth of Pten −/− ES cells in vivo, suggesting that AKT-1 plays an essential role in PTEN-controlled tumorigenesis.

Analysis of the role of interleukin-1β (IL-1β)in vivo by gene targeting in embryonic stem (ES) cells

Cytokine ◽  
1994 ◽  
Vol 6 (5) ◽  
pp. 574
Author(s):  
L. Shornick ◽  
P. De Togni ◽  
S. Mariathasan ◽  
A. Fick ◽  
J. Goellner ◽  
...  
Keyword(s):  
Gene Targeting ◽  
Es Cells ◽  
Embryonic Stem ◽  
Interleukin 1Β

scholarly journals MOZ and BMI1 play opposing roles during Hox gene activation in ES cells and in body segment identity specification in vivo

2015 ◽  
Vol 112 (17) ◽  
pp. 5437-5442 ◽  
Author(s):  
Bilal N. Sheikh ◽  
Natalie L. Downer ◽  
Belinda Phipson ◽  
Hannah K. Vanyai ◽  
Andrew J. Kueh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Es Cells ◽  
Gene Activation ◽  
Embryonic Stem ◽  
Mrna Levels ◽  
Body Segment ◽  
Initial Activation ◽  
Activation Phase

Hox genes underlie the specification of body segment identity in the anterior–posterior axis. They are activated during gastrulation and undergo a dynamic shift from a transcriptionally repressed to an active chromatin state in a sequence that reflects their chromosomal location. Nevertheless, the precise role of chromatin modifying complexes during the initial activation phase remains unclear. In the current study, we examined the role of chromatin regulators during Hox gene activation. Using embryonic stem cell lines lacking the transcriptional activator MOZ and the polycomb-family repressor BMI1, we showed that MOZ and BMI1, respectively, promoted and repressed Hox genes during the shift from the transcriptionally repressed to the active state. Strikingly however, MOZ but not BMI1 was required to regulate Hox mRNA levels after the initial activation phase. To determine the interaction of MOZ and BMI1 in vivo, we interrogated their role in regulating Hox genes and body segment identity using Moz;Bmi1 double deficient mice. We found that the homeotic transformations and shifts in Hox gene expression boundaries observed in single Moz and Bmi1 mutant mice were rescued to a wild type identity in Moz;Bmi1 double knockout animals. Together, our findings establish that MOZ and BMI1 play opposing roles during the onset of Hox gene expression in the ES cell model and during body segment identity specification in vivo. We propose that chromatin-modifying complexes have a previously unappreciated role during the initiation phase of Hox gene expression, which is critical for the correct specification of body segment identity.

scholarly journals Evolutionarily Conserved Role of Nucleostemin: Controlling Proliferation of Stem/Progenitor Cells during Early Vertebrate Development

2006 ◽  
Vol 26 (24) ◽  
pp. 9291-9301 ◽  
Author(s):  
Chantal Beekman ◽  
Massimo Nichane ◽  
Sarah De Clercq ◽  
Marion Maetens ◽  
Thomas Floss ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Embryonic Stem Cells ◽  
Progenitor Cells ◽  
Control Cell ◽  
Embryonic Stem ◽  
Physiological Role ◽  
Specific Gene

ABSTRACT Nucleostemin (NS) is a putative GTPase expressed preferentially in the nucleoli of neuronal and embryonic stem cells and several cancer cell lines. Transfection and knockdown studies indicated that NS controls the proliferation of these cells by interacting with the p53 tumor suppressor protein and regulating its activity. To assess the physiological role of NS in vivo, we generated a mutant mouse line with a specific gene trap event that inactivates the NS allele. The corresponding NS −/− embryos died around embryonic day 4. Analyses of NS mutant blastocysts indicated that NS is not required to maintain pluripotency, nucleolar integrity, or survival of the embryonic stem cells. However, the homozygous mutant blastocysts failed to enter S phase even in the absence of functional p53. Haploid insufficiency of NS in mouse embryonic fibroblasts leads to decreased cell proliferation. NS also functions in early amphibian development to control cell proliferation of neural progenitor cells. Our results show that NS has a unique ability, derived from an ancestral function, to control the proliferation rate of stem/progenitor cells in vivo independently of p53.

scholarly journals The Multiple Faces of MNT and Its Role as a MYC Modulator

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4682
Author(s):  
Judit Liaño-Pons ◽  
Marie Arsenian-Henriksson ◽  
Javier León
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Repression ◽  
Cell Biology ◽  
Essential Role ◽  
Present Knowledge ◽  
Special Focus ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Tumor Cell Survival

MNT is a crucial modulator of MYC, controls several cellular functions, and is activated in most human cancers. It is the largest, most divergent, and most ubiquitously expressed protein of the MXD family. MNT was first described as a MYC antagonist and tumor suppressor. Indeed, 10% of human tumors present deletions of one MNT allele. However, some reports show that MNT functions in cooperation with MYC by maintaining cell proliferation, promoting tumor cell survival, and supporting MYC-driven tumorigenesis in cellular and animal models. Although MAX was originally considered MNT’s obligate partner, our recent findings demonstrate that MNT also works independently. MNT forms homodimers and interacts with proteins both outside and inside of the proximal MYC network. These complexes are involved in a wide array of cellular processes, from transcriptional repression via SIN3 to the modulation of metabolism through MLX as well as immunity and apoptosis via REL. In this review, we discuss the present knowledge of MNT with a special focus on its interactome, which sheds light on the complex and essential role of MNT in cell biology.

scholarly journals Depletion of the 110-Kilodalton Isoform of Poly(ADP-Ribose) Glycohydrolase Increases Sensitivity to Genotoxic and Endotoxic Stress in Mice

2004 ◽  
Vol 24 (16) ◽  
pp. 7163-7178 ◽  
Author(s):  
Ulrich Cortes ◽  
Wei-Min Tong ◽  
Donna L. Coyle ◽  
Mirella L. Meyer-Ficca ◽  
Ralph G. Meyer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Alkylating Agents ◽  
Endotoxic Shock ◽  
Embryonic Stem ◽  
Cellular Processes ◽  
Streptozotocin Induced Diabetes ◽  
The Impact ◽  
Parp 1

ABSTRACT Poly(ADP-ribosylation) is rapidly stimulated in cells following DNA damage. This posttranslational modification is regulated by the synthesizing enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG). Although the role of PARP-1 in response to DNA damage has been studied extensively, the function of PARG and the impact of poly(ADP-ribose) homeostasis in various cellular processes are largely unknown. Here we show that by gene targeting in embryonic stem cells and mice, we specifically deleted the 110-kDa PARG protein (PARG110) normally found in the nucleus and that depletion of PARG110 severely compromised the automodification of PARP-1 in vivo. PARG110-deficient mice were viable and fertile, but these mice were hypersensitive to alkylating agents and ionizing radiation. In addition, these mice were susceptible to streptozotocin-induced diabetes and endotoxic shock. These data indicate that PARG110 plays an important role in DNA damage responses and in pathological processes.

scholarly journals The Nuclear Scaffold Protein NIPP1 Is Essential for Early Embryonic Development and Cell Proliferation

2004 ◽  
Vol 24 (13) ◽  
pp. 5863-5874 ◽  
Author(s):  
Aleyde Van Eynde ◽  
Mieke Nuytten ◽  
Mieke Dewerchin ◽  
Luc Schoonjans ◽  
Stefaan Keppens ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Embryonic Development ◽  
Protein Phosphatase ◽  
Cultured Cells ◽  
Es Cells ◽  
Embryonic Stem ◽  
Scaffold Protein ◽  
Early Embryonic Development ◽  
Nuclear Scaffold

ABSTRACT NIPP1 (nuclear inhibitor of protein phosphatase 1) is a ubiquitously expressed nuclear scaffold protein that has been implicated in both transcription and RNA processing. Among its protein ligands are a protein kinase, a protein phosphatase, two splicing factors, and a transcriptional regulator, and the binding of these proteins to NIPP1 is tightly regulated by phosphorylation. To study the function of NIPP1 in vivo, we have used homologous recombination to generate mice that are deficient in NIPP1. NIPP1−/+ mice developed normally. However, NIPP1−/− embryos showed severely retarded growth at embryonic day 6.5 (E6.5) and were resorbed by E8.5. This early embryonic lethality was not associated with increased apoptosis but correlated with impaired cell proliferation. Blastocyst outgrowth experiments and the RNA interference-mediated knockdown of NIPP1 in cultured cells also revealed an essential role for NIPP1 in cell proliferation. In further agreement with this function, no viable NIPP1−/− cell lines were obtained by derivation of embryonic stem (ES) cells from blastocysts of NIPP1−/+ intercrosses or by forced homogenotization of heterozygous ES cells at high concentrations of Geneticin. We conclude that NIPP1 is indispensable for early embryonic development and cell proliferation.

scholarly journals Increased extracellular signal regulated kinases phosphorylation in the adrenal gland in response to chronic ACTH treatment

2007 ◽  
Vol 192 (3) ◽  
pp. 647-658 ◽  
Author(s):  
Jorge G Ferreira ◽  
Célia D Cruz ◽  
Delminda Neves ◽  
Duarte Pignatelli
Keyword(s):  
Cell Proliferation ◽  
Mek Inhibitor ◽  
Nuclear Antigen ◽  
Dependent Manner ◽  
Cellular Processes ◽  
Extracellular Signal ◽  
Extracellular Stimuli ◽  
Corticosterone Release

ACTH released from the pituitary acts through activation of cAMP/PKA in adrenocortical cells stimulating steroidogenesis. Although ACTH was originally thought to have anti-proliferative effects on the adrenal, recently it has been described that it could also have proliferative effects acting through other signalling cascades. This is also relevant in humans given the increased levels of ACTH occurring together with adrenal cortex hyperplasia observed in Cushing’s disease and possibly in other situations such as chronic stress. One of the signalling pathways regulating cell proliferation is the extracellular signal regulated kinase (ERKs) pathway. ERKs are members of the MAPK family of cascades. They are activated by extracellular stimuli such as growth factors and mitogens, become phosphorylated through MEK1/2 and regulate a diversity of cellular processes such as proliferation and differentiation. Until now, no study addressed the effects of chronic ACTH administration on the activation of ERKs in vivo. Using rats submitted to different ACTH dosages as well as variable durations, we determined if ACTH induced ERKs activation and by establishing a parallelism with proliferating cell nuclear antigen (PCNA) expression, we aimed to demonstrate a role of ACTH-induced ERKs activation in cell proliferation. Blood was collected for hormonal analysis and the role of ACTH-induced ERKs activation in the stimulation of steroidogenesis was also studied. We confirmed that ACTH increased adrenal weight and corticosterone levels when compared with control or dexamethasone-treated animals. We also demonstrated that ACTH increases ERKs activation and PCNA expression in a time- and dose-dependent manner. When ERKs activation was blocked by the use of a specific MEK inhibitor (PD98059), there was a decrease in ACTH-induced corticosterone release and PCNA expression. We conclude that chronic ACTH induces ERKs activation and that this plays an important role in the induction of cell proliferation as well as steroidogenesis.

scholarly journals Multiple ribonuclease A family members cleave transfer RNAs in response to stress

2019 ◽  
Author(s):  
Yasutoshi Akiyama ◽  
Shawn Lyons ◽  
Marta M. Fay ◽  
Takaaki Abe ◽  
Paul Anderson ◽  
...  
Keyword(s):  
Cell Survival ◽  
Family Members ◽  
Rnase A ◽  
Transfer Rnas ◽  
Cellular Processes ◽  
Stress Changes ◽  
Response To Stress ◽  
Rnase A Superfamily

ABSTRACTDuring stress, changes in gene expression are critical for cell survival. Stress-induced tRNA cleavage has been implicated in various cellular processes, where tRNA fragments play diverse regulatory roles. Angiogenin (ANG), a member of the RNase A superfamily, induces cleavage of tRNAs resulting in the formation of tRNA-derived stress-induced RNAs (tiRNAs) that contribute to translational reprogramming aiming at cell survival. The role of other stress-induced RNases in tRNA cleavage is poorly understood. Using gene editing and biochemical approaches, we show that other members of the RNase A family are capable of targeting tRNAs in stress-responsive manner. We show that in the absence of ANG, these RNases also promote the production of tiRNAs. Moreover, specific stresses (such as treatment with sodium arsenite) activate cleavage of universal 3’-CCA termini of tRNAs in ANG-independent fashion in living cells. We conclude that multiple RNase A family members are capable of targeting tRNAs in a stress-specific manner in vivo.

scholarly journals Circadian Clock Gene Plays a Key Role on Ovarian Cycle and Spontaneous Abortion

2015 ◽  
Vol 37 (3) ◽  
pp. 911-920 ◽  
Author(s):  
Ruiwen Li ◽  
Shuting Cheng ◽  
Zhengrong Wang
Keyword(s):  
Protein Interactions ◽  
Clock Gene ◽  
Es Cells ◽  
Embryonic Stem ◽  
Clock Gene Expression ◽  
Induced Apoptosis ◽  
Mes Cells

Background/Aims: Circadian locomotor output cycles protein kaput (CLOCK) plays a key role in maintaining circadian rhythms and activation of downstream elements. However, its function on human female reproductive system remains unknown. Methods: To investigate the potential role of CLOCK, CLOCK-shRNAs were transfected into mouse 129 ES cells or injected into the ovaries of adult female mice. Western blotting was utilized to analyze the protein interactions and flow cytometry was used to assess apoptosis. Results: The expression of CLOCK peaked at the 6th week in the healthy fetuses. However, an abnormal expression of CLOCK was detected in fetuses from spontaneous miscarriage. To determine the effect of CLOCK on female fertility, a small hairpin RNA (shRNA) strategy was used to specifically knockdown the CLOCK gene expression in vitro and in vivo. Knockdown of CLOCK induced apoptosis in mouse embryonic stem (mES) cells and inhibited the proliferation in mES cells in vitro. CLOCK knockdown also led to decreased release of oocytes and smaller litter size compared with control in vivo. Conclusions: Collectively, theses findings indicate that CLOCK plays an important role in fertility and that the CLOCK knockdown leads to reduction in reproduction and increased miscarriage risk.

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