Endothelin‐1 and α‐melanocortin have redundant effects on global genome repair in UV‐irradiated human melanocytes despite distinct signaling pathways

2019 ◽  
Vol 33 (2) ◽  
pp. 293-304 ◽  
Author(s):  
Viki B. Swope ◽  
Renny J. Starner ◽  
Corinne Rauck ◽  
Zalfa A. Abdel‐Malek
Keyword(s):  
Signaling Pathways ◽  
Endothelin 1 ◽  
Human Melanocytes ◽  
Global Genome Repair ◽  
Genome Repair

scholarly journals YAP and endothelin-1 signaling: an emerging alliance in cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Piera Tocci ◽  
Giovanni Blandino ◽  
Anna Bagnato
Keyword(s):  
Signaling Pathways ◽  
Cell Fate ◽  
Therapeutic Option ◽  
Hippo Pathway ◽  
Signaling Network ◽  
Nuclear Accumulation ◽  
Binding Motif ◽  
Mutant P53 ◽  
Endothelin 1 ◽  
The Hippo Pathway

AbstractThe rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA receptor (ETAR) and ETB receptor (ETBR) that belong to the GPCR superfamily, affect both cancer initiation and progression in a variety of cancer types. By the cross-talking with multiple signaling pathways mainly through the scaffold protein β-arrestin1 (β-arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the Hippo pathway. In ETAR highly expressing tumors ET-1 axis induces the de-phosphorylation and nuclear accumulation of the Hippo pathway downstream effectors, the paralogous transcriptional cofactors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Recent evidence have discovered that ET-1R/β-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network. Mechanistically, YAP and mutp53 are enrolled in nuclear complexes that turn on a highly selective YAP/mutp53-dependent transcriptional response. Notably, ET-1R blockade by the FDA approved dual ET-1 receptor antagonist macitentan interferes with ET-1R/YAP/mutp53 signaling interplay, through the simultaneous suppression of YAP and mutp53 functions, hampering metastasis and therapy resistance. Based on these evidences, we aim to review the recent findings linking the GPCR signaling, as for ET-1R, to YAP/TAZ signaling, underlining the clinical relevance of the blockade of such signaling network in the tumor and microenvironmental contexts. In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers. The identification of ET-1R/β-arr1-intertwined and bi-directional signaling pathways as targetable vulnerabilities, may open new therapeutic approaches able to disable the ET-1R-orchestrated YAP/mutp53 signaling network in both tumor and stromal cells and concurrently sensitizes to high-efficacy combined therapeutics.

scholarly journals Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction

2019 ◽  
Vol 317 (5) ◽  
pp. H1166-H1172 ◽  
Author(s):  
T. Dylan Olver ◽  
Zachary I. Grunewald ◽  
Thaysa Ghiarone ◽  
Robert M. Restaino ◽  
Allan R. K. Sales ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Insulin Signaling ◽  
Relative Increase ◽  
Resistance Arteries ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Stimulation ◽  
Receptor Antagonism ◽  
Endothelin 1 ◽  
Pi3k Activation ◽  
Obese Subjects

Insulin modulates vasomotor tone through vasodilator and vasoconstrictor signaling pathways. The purpose of the present work was to determine whether insulin-stimulated vasoconstriction is a pathophysiological phenomenon that can result from a combination of persistent insulin signaling, suppressed phosphatidylinositol-3 kinase (PI3K) activation, and an ensuing relative increase in MAPK/endothelin-1 (ET-1) activity. First, we examined previously published work from our group where we assessed changes in lower-limb blood flow in response to an oral glucose tolerance test (endogenous insulin stimulation) in lean and obese subjects. The new analyses showed that the peak rise in vascular resistance during the postprandial state was greater in obese compared with lean subjects. We next extended on these findings by demonstrating that insulin-induced vasoconstriction in isolated resistance arteries from obese subjects was attenuated with ET-1 receptor antagonism, thus implicating ET-1 signaling in this constriction response. Last, we examined in isolated resistance arteries from pigs the dual roles of persistent insulin signaling and blunted PI3K activation in modulating vasomotor responses to insulin. We found that prolonged insulin stimulation did not alter vasomotor responses to insulin when insulin-signaling pathways remained unrestricted. However, prolonged insulinization along with pharmacological suppression of PI3K activity resulted in insulin-induced vasoconstriction, rather than vasodilation. Notably, such aberrant vascular response was rescued with either MAPK inhibition or ET-1 receptor antagonism. In summary, we demonstrate that insulin-induced vasoconstriction is a pathophysiological phenomenon that can be recapitulated when sustained insulin signaling is coupled with depressed PI3K activation and the concomitant relative increase in MAPK/ET-1 activity. NEW & NOTEWORTHY This study reveals that insulin-induced vasoconstriction is a pathophysiological phenomenon. We also provide evidence that in the setting of persistent insulin signaling, impaired phosphatidylinositol-3 kinase activation appears to be a requisite feature precipitating MAPK/endothelin 1-dependent insulin-induced vasoconstriction.

scholarly journals Defective Global Genome Repair in XPC Mice Is Associated with Skin Cancer Susceptibility But Not with Sensitivity to UVB Induced Erythema and Edema

1998 ◽  
Vol 110 (4) ◽  
pp. 405-409 ◽  
Author(s):  
Rob J.W. Berg ◽  
Hendrik J.T. Ruven ◽  
Arthur T. Sands ◽  
Frank R. de Gruijl ◽  
Leon H.F. Mullenders
Keyword(s):  
Skin Cancer ◽  
Cancer Susceptibility ◽  
Global Genome Repair ◽  
Genome Repair

scholarly journals Arenarol isolated from a marine sponge abrogates endothelin-1-stimulated melanogenesis by interrupting MEK phosphorylation in normal human melanocytes

2013 ◽  
Vol 65 (6) ◽  
pp. 915-926 ◽  
Author(s):  
Bong-Keun Choi ◽  
Byung-Yoon Cha ◽  
Takeshi Fujiwara ◽  
Akihiko Kanamoto ◽  
Je-Tae Woo ◽  
...  
Keyword(s):  
Marine Sponge ◽  
Endothelin 1 ◽  
Human Melanocytes ◽  
Normal Human
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