Abstract 5983: p38 kinase acts as a negative regulator of recurrence after surgery in a mammary carcinoma model, through apoptosis induction and proliferation inhibition

2020 ◽  
Author(s):  
Carla S. Capobianco ◽  
Maria F. Gottardo ◽  
Johanna E. Sidabra ◽  
Julio A. Aguirre Ghiso ◽  
Daniel F. Alonso ◽  
...  
Keyword(s):  
Mammary Carcinoma ◽  
Negative Regulator ◽  
Proliferation Inhibition ◽  
Apoptosis Induction ◽  
P38 Kinase

scholarly journals Abstract 78: p38 kinase is a negative regulator of tumorigenesis and recurrence after surgery in a mammary carcinoma model

2018 ◽  
Author(s):  
Carla S. Capobianco ◽  
Johanna E. Sidabra ◽  
Maria F. Gottardo ◽  
Julio A. Aguirre-Ghiso ◽  
Daniel F. Alonso ◽  
...  
Keyword(s):  
Mammary Carcinoma ◽  
Negative Regulator ◽  
P38 Kinase

scholarly journals Interplay between Mdm2 and HIPK2 in the DNA damage response

2014 ◽  
Vol 11 (96) ◽  
pp. 20140319 ◽  
Author(s):  
Xiao-Peng Zhang ◽  
Feng Liu ◽  
Wei Wang
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Negative Regulator ◽  
Critical Event ◽  
Apoptosis Induction ◽  
Nuclear Entry ◽  
Induce Cell Cycle Arrest ◽  
Interacting Protein ◽  
Cycle Arrest ◽  
Damage Response

The tumour suppressor p53 is activated to induce cell-cycle arrest or apoptosis in the DNA damage response (DDR). p53 phosphorylation at Ser46 by HIPK2 (homeodomain-interacting protein kinase 2) is a critical event in apoptosis induction. Interestingly, HIPK2 is degraded by Mdm2 (a negative regulator of p53), whereas Mdm2 is downregulated by HIPK2 through several mechanisms. Here, we develop a four-module network model for the p53 pathway to clarify the role of interplay between Mdm2 and HIPK2 in the DDR evoked by ultraviolet radiation. By numerical simulations, we reveal that Mdm2-dependent HIPK2 degradation promotes cell survival after mild DNA damage and that inhibition of HIPK2 degradation is sufficient to trigger apoptosis. In response to severe damage, p53 phosphorylation at Ser46 is promoted by the accumulation of HIPK2 due to downregulation of nuclear Mdm2 in the later phase of the response. Meanwhile, the concentration of p53 switches from moderate to high levels, contributing to apoptosis induction. We show that the presence of three mechanisms for Mdm2 downregulation, i.e. repression of mdm2 expression, inhibition of its nuclear entry and HIPK2-induced degradation, guarantees the apoptosis of irreparably damaged cells. Our results agree well with multiple experimental observations, and testable predictions are also made. This work advances our understanding of the regulation of p53 activity in the DDR and suggests that HIPK2 should be a significant target for cancer therapy.

scholarly journals Small molecule inhibition of Csk alters affinity recognition by T cells

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Boryana N Manz ◽  
Ying Xim Tan ◽  
Adam H Courtney ◽  
Florentine Rutaganira ◽  
Ed Palmer ◽  
...  
Keyword(s):  
T Cells ◽  
Catalytic Activity ◽  
T Cell ◽  
Small Molecule ◽  
Src Family Kinases ◽  
Negative Regulator ◽  
Proliferation Inhibition ◽  
Tcr Signaling ◽  
Cell Responses ◽  
Small Molecule Inhibition

The C-terminal Src kinase (Csk), the primary negative regulator of Src-family kinases (SFK), plays a crucial role in controlling basal and inducible receptor signaling. To investigate how Csk activity regulates T cell antigen receptor (TCR) signaling, we utilized a mouse expressing mutated Csk (CskAS) whose catalytic activity is specifically and rapidly inhibited by a small molecule. Inhibition of CskAS during TCR stimulation led to stronger and more prolonged TCR signaling and to increased proliferation. Inhibition of CskAS enhanced activation by weak but strictly cognate agonists. Titration of Csk inhibition revealed that a very small increase in SFK activity was sufficient to potentiate T cell responses to weak agonists. Csk plays an important role, not only in basal signaling, but also in setting the TCR signaling threshold and affinity recognition.

scholarly journals Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells

2017 ◽  
Vol 50 (4) ◽  
pp. 1299-1311 ◽  
Author(s):  
Ke-Wei Ren ◽  
Ya-Hua Li ◽  
Gang Wu ◽  
Jian-Zhuang Ren ◽  
Hui-Bin Lu ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Proliferation Inhibition ◽  
Apoptosis Induction ◽  
Liver Cancer Cells

scholarly journals Activin Inhibits the Human Pit-1 Gene Promoter through the p38 Kinase Pathway in a Smad-Independent Manner

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4351-4362 ◽  
Author(s):  
Chantal de Guise ◽  
Annie Lacerte ◽  
Shahrzad Rafiei ◽  
Rachel Reynaud ◽  
Melanie Roy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pituitary Gland ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Critical Role ◽  
Gene Promoter ◽  
Negative Regulator ◽  
P38 Kinase ◽  
P38 Mapk Pathway ◽  
Lactotrope Cells

The pituitary transcription factor Pit-1 regulates hormonal production from the anterior pituitary gland. However, the mechanisms by which Pit-1 gene expression is regulated in humans are poorly understood. Activin, a member of the TGFβ superfamily, acts as a negative regulator of cell growth and prolactin gene expression in lactotrope cells. In this study, we show that activin negatively regulates the human Pit-1 gene promoter. We defined a 117-bp element within the Pit-1 promoter that is sufficient to relay these inhibitory effects. We further investigated the signaling pathways that mediate activin-induced inhibition of Pit-1 gene promoter in pituitary lactotrope cells. We found that the activin effects on Pit-1 gene regulation are Smad independent and require the p38 MAPK pathway. Specifically, blocking p38 kinase activity reverses activin-mediated inhibition of the Pit-1 gene promoter. Together, our results highlight the p38 MAPK pathway as a key regulator of activin function in pituitary lactotrope cells and further emphasizes the critical role played by activin in regulating hormonal production in the pituitary gland.

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