Endoderm development requires centrioles to restrain p53-mediated apoptosis in the absence of ERK activity

Abstract Background Interleukin-6 (IL6) was recently identified as an embryotrophic factor in bovine embryos, where it acts primarily to mediate inner cell mass (ICM) size. This work explored whether IL6 affects epiblast (EPI) and primitive endoderm (PE) development, the two embryonic lineages generated from the ICM after its formation. Nuclear markers for EPI (NANOG) and PE (GATA6) were used to differentiate the two cell types. Results Increases (P < 0.05) in total ICM cell numbers and PE cell numbers were detected in bovine blastocysts at day 8 and 9 post-fertilization after exposure to 100 ng/ml recombinant bovine IL6. Also, IL6 increased (P < 0.05) the number of undifferentiated ICM cells (cells containing both PE and EPI markers). The effects of IL6 on EPI cell numbers were inconsistent. Studies were also completed to explore the importance of Janus kinase 2 (JAK2)-dependent signaling in bovine PE cells. Definitive activation of STAT3, a downstream target for JAK2, was observed in PE cells. Also, pharmacological inhibition of JAK2 decreased (P < 0.05) PE cell numbers. Conclusions To conclude, IL6 manipulates ICM development after EPI/PE cell fates are established. The PE cells are the target for IL6, where a JAK-dependent signal is used to regulate PE numbers.

cMyc and ERK activity are associated with resistance to ALK inhibitory treatment in glioblastoma

Journal of Neuro-Oncology ◽

10.1007/s11060-019-03348-z ◽

2019 ◽

Vol 146 (1) ◽

pp. 9-23

Author(s):

Anne Berberich ◽

Lara-Marie Schmitt ◽

Stefan Pusch ◽

Thomas Hielscher ◽

Petra Rübmann ◽

...

Keyword(s):

Erk Activity

Pancreatic Tumor Cells with Mutant K-ras Suppress ERK Activity by MEK-Dependent Induction of MAP Kinase Phosphatase-2

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2001.4243 ◽

2001 ◽

Vol 280 (4) ◽

pp. 992-997 ◽

Cited By ~ 48

Author(s):

Michele T. Yip-Schneider ◽

Amy Lin ◽

Mark S. Marshall

Keyword(s):

Map Kinase ◽

Tumor Cells ◽

Pancreatic Tumor ◽

Map Kinase Phosphatase ◽

Erk Activity

β-Arrestin Scaffolding of the ERK Cascade Enhances Cytosolic ERK Activity but Inhibits ERK-mediated Transcription following Angiotensin AT1a Receptor Stimulation

Journal of Biological Chemistry ◽

10.1074/jbc.m106457200 ◽

2002 ◽

Vol 277 (11) ◽

pp. 9429-9436 ◽

Cited By ~ 277

Author(s):

Akira Tohgo ◽

Kristen L. Pierce ◽

Eric W. Choy ◽

Robert J. Lefkowitz ◽

Louis M. Luttrell

Keyword(s):

Receptor Stimulation ◽

At1a Receptor ◽

Erk Activity

Odd skipped related 1is a negative feedback regulator of nodal-induced endoderm development

Developmental Dynamics ◽

10.1002/dvdy.24191 ◽

2014 ◽

Vol 243 (12) ◽

pp. 1571-1580 ◽

Cited By ~ 7

Author(s):

Alexandra V. Terashima ◽

Sudha P. Mudumana ◽

Iain A. Drummond

Keyword(s):

Negative Feedback ◽

Endoderm Development ◽

Feedback Regulator

Transactivation of the Epidermal Growth Factor Receptor Is Involved in 12-O-Tetradecanoylphorbol-13-acetate-induced Signal Transduction

Journal of Biological Chemistry ◽

10.1074/jbc.m107156200 ◽

2001 ◽

Vol 276 (50) ◽

pp. 46722-46728 ◽

Cited By ~ 48

Author(s):

Nanyue Chen ◽

Wei-Ya Ma ◽

Qing-Bai She ◽

Erxi Wu ◽

Guangming Liu ◽

...

Keyword(s):

Signal Transduction ◽

Epidermal Growth Factor Receptor ◽

Cell Transformation ◽

Growth Factor Receptor ◽

Tumor Promotion ◽

Binding Activity ◽

Heparin Binding ◽

Epidermal Growth ◽

Induced Signal ◽

Erk Activity

The mechanism of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion is still not well understood even though it is thought to be related to the protein kinase C/mitogen-activated protein kinase/AP-1 pathway. Recently, TPA was also found to induce epidermal growth factor receptor (EGFR) activity. Here, we investigated whether the EGFR is a necessary component for TPA-induced signal transduction associated with tumor promotion. We demonstrated that potent inhibitors of the EGFR, PD153035 and AG1478, blocked TPA-induced phosphorylation of extracellular signal-regulated kinases (ERKs), AP-1 activity, and cell transformation.Egfrgene deficiency blocked TPA-induced ERK activity and AP-1 binding activity. The blocking of the ectodomain of the EGFR by a monoclonal antibody depressed TPA-induced ERK activity and AP-1 DNA binding activity. The use of a neutralizing antibody for heparin-binding EGF, one of the ligands of EGFR, blocked TPA-induced phosphorylation of ERKs. BB-94, a potent inhibitor of matrix metalloproteinases, which are activators of ectodomain shedding of EGFR ligands, also blocked TPA-induced ERK activity, AP-1 DNA binding, and cell transformation but had no effect on EGF-induced signal transduction. Anti-EGFR, anti-heparin-binding EGF, and BB-94 each blocked TPA-induced EGFR phosphorylation, but only anti-EGFR could block EGF-induced EGFR phosphorylation. Based on these results, we conclude that the EGFR is required for mediating TPA-induced signal transduction. EGFR transactivation induced by TPA is a mechanism by which the EGFR mediates TPA-induced tumor promotion-related signal transduction.

Cell proliferation is insufficient, but loss of tuberin is necessary, for chemically induced nephrocarcinogenicity

AJP Renal Physiology ◽

10.1152/ajprenal.00261.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. F262-F270 ◽

Cited By ~ 11

Author(s):

Hae-Seong Yoon ◽

Terrence J. Monks ◽

Jeffrey I. Everitt ◽

Cheryl L. Walker ◽

Serrine S. Lau

Keyword(s):

Cell Proliferation ◽

Tissue Injury ◽

Tumor Development ◽

Suppressor Gene ◽

Tumor Formation ◽

Renal Tumors ◽

Outer Stripe ◽

Acute Tissue Injury ◽

Cell Cycle Deregulation ◽

Erk Activity

Although 2,3,5-tris-(glutathion- S-yl)hydroquinone (TGHQ; 2.5 μmol/kg ip) markedly increased cell proliferation within the outer stripe of the outer medulla (OSOM) of the kidney in both wild-type ( Tsc2+/+ ) and mutant Eker rats ( Tsc2 EK/+), only TGHQ-treated Tsc2 EK/+ rats developed renal tumors, indicating that cell proliferation per se was not sufficient for tumor development. Tuberin expression was initially induced within the OSOM after TGHQ treatment but was lost within TGHQ-induced renal tumors. High extracellular signal-regulated kinase (ERK) activity occurred in the OSOM of Tsc2 EK/+ rats at 4 mo and in TGHQ-induced renal tumors. Cyclin D1 was also highly expressed in TGHQ-induced renal tumors. Reexpression of Tsc2 in tuberin-negative cells decreased ERK activity, consistent with the growth-suppressive effects of this tumor suppressor gene. Thus 1) stimulation of cell proliferation after toxicant insult is insufficient for tumor formation; 2) tuberin induction after acute tissue injury suggests that Tsc2 is an acute-phase response gene, limiting the proliferative response after injury; and 3) loss of Tsc2 gene function is associated with cell cycle deregulation.

Multiple sources of signal amplification within the B cell Ras/MAPK pathway

10.1101/415737 ◽

2018 ◽

Author(s):

Justin D. Mclaurin ◽

Orion D. Weiner

Keyword(s):

Positive Feedback ◽

Signal Amplification ◽

Mapk Pathway ◽

Threshold Level ◽

Cell Types ◽

Multiple Sources ◽

Analog To Digital ◽

Ras Activation ◽

Wide Range ◽

Erk Activity

AbstractThe Ras-Map kinase (MAPK) cascade underlies functional decisions in a wide range of cell types and organisms. In B cells, positive feedback-driven Ras activation is the proposed source of the digital (all-or-none) MAPK responses following antigen stimulation. However, an inability to measure endogenous Ras activity in living cells has hampered our ability to test this model directly. Here we leverage biosensors of endogenous Ras and ERK activity to revisit this question. We find that BCR ligation drives switch-like Ras activation and that lower BCR signaling output is required for the maintenance versus the initiation of Ras activation. Surprisingly, digital ERK responses persist in the absence of positive feedback-mediated Ras activation, and digital ERK is observed at a threshold level of Ras activation. These data suggest an independent analog-to-digital switch downstream of Ras activation, and reveals that multiple sources of signal amplification exist within the Ras-ERK module of the BCR pathway.