Excess centrosomes induce p53‐dependent senescence without DNA damage in endothelial cells

Yu, Zhixian; Ruter, Dana L.; Kushner, Erich J.; Bautch, Victoria L.

doi:10.1096/fj.201601320r

Cited by 9 publications

(10 citation statements)

References 51 publications

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“…2B ). The results suggested that the activation of the P53/P21 pathway, mediated by the DNA damage response, could underlay the senescence of A375 cells as reported 14 , 15 .…”

Section: Resultsmentioning

confidence: 76%

Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway

et al. 2018

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Although targeted therapy and immunotherapy greatly improve the outcome of melanoma, drug resistance and low response rates still maintain the unsubstitutability of traditional chemotherapy. Cisplatin (CDDP) is widely used in different types of tumours with high response rates, but it generally has low efficiency in melanoma. The mechanisms underpinning the phenomena are not sufficiently understood. Here we demonstrated that various melanoma cell lines adopted senescence phenotype after CDDP treatment in contrast to the other types of tumour cells. CDDP treatment induced melanoma A375 cells into senescence through the sequential activation of the DNA damage response and the P53/P21 pathway. All the senescent melanoma cells induced by CDDP alone or the combination of CDDP and dacarbazine developed robust senescence-associated secretory phenotype (SASP), that is, the secretion of multiple cytokines. IL-1α was an early component and an upstream regulator of SASP. Similarly, CDDP either alone or combined with dacarbazine could induce melanoma cell senescence and SASP in either A375 or B16F10 melanoma xenograft mice. The supernatant of senescent A375 cells promoted the growth of normal non-senescent A375 cells and enhanced their expression and secretion of IL-8 through the activation of the ERK1/2-RSK1 pathway. The transplantation of non-senescent and senescent A375 cells together into nude mice showed accelerated tumour growth compared with transplanting non-senescent cells alone; no tumours developed when transplanting senescent cells alone. Following CDDP administration in A375-bearing mice, the intratumour injection of neutralisation antibodies targeting the SASP factors IL-1α or IL-8 evidently delayed tumour growth. The results suggest that the CDDP-induced senescent melanoma cells promote non-senescent cells proliferation through the activation of ERK1/2-RSK1 pathway by the SASP factors. Cell senescence and concomitant SASP may be the particular mechanisms for melanoma to resist chemotherapeutics.

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“…2B ). The results suggested that the activation of the P53/P21 pathway, mediated by the DNA damage response, could underlay the senescence of A375 cells as reported 14 , 15 .…”

Section: Resultsmentioning

confidence: 76%

Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway

et al. 2018

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“…All cells were maintained at 37 °C and 5% CO 2 . Tetracycline-inducible Plk4 overexpression HUVEC were generated as previously described [13,17,25]. Viruses were produced by the UNC Lenti-shRNA Core Facility.…”

Section: Cell Culturementioning

confidence: 99%

Excess centrosomes disrupt vascular lumenization and endothelial cell adherens junctions

et al. 2020

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Proper blood vessel formation requires coordinated changes in endothelial cell polarity and rearrangement of cell–cell junctions to form a functional lumen. One important regulator of cell polarity is the centrosome, which acts as a microtubule organizing center. Excess centrosomes perturb aspects of endothelial cell polarity linked to migration, but whether centrosome number influences apical–basal polarity and cell–cell junctions is unknown. Here, we show that excess centrosomes alter the apical–basal polarity of endothelial cells in angiogenic sprouts and disrupt endothelial cell–cell adherens junctions. Endothelial cells with excess centrosomes had narrower lumens in a 3D sprouting angiogenesis model, and zebrafish intersegmental vessels had reduced perfusion following centrosome overduplication. These results indicate that endothelial cell centrosome number regulates proper lumenization downstream of effects on apical–basal polarity and cell–cell junctions. Endothelial cells with excess centrosomes are prevalent in tumor vessels, suggesting how centrosomes may contribute to tumor vessel dysfunction.

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“…BrdU incorporation was an adaptation (Yu et al, 2017). Briefly, HUVEC were incubated with 10 µM BrdU (Millipore Sigma, #B5002) in flow media for the last 90 min of flow and fixed in ice-cold 100% methanol.…”

Section: Immunofluorescencementioning

confidence: 99%

SMAD6 Integrates Endothelial Cell Homeostatic Flow Responses Downstream of Notch

Ruter

Liu²,

Ngo³

et al. 2020

Preprint

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ABSTRACTLaminar shear stress regulates blood vessel morphogenesis and subsequent quiescence, leading to vascular homeostasis. Although important for vessel function, how vascular homeostasis is set up and maintained is poorly understood. SMAD6, a scaffold for several signaling pathways, is expressed in developing arteries and its expression is flow-regulated. We found that SMAD6 is essential for endothelial cell flow-mediated responses downstream of the mechanosensor Notch1. Endothelial cells with reduced SMAD6 levels failed to align under homeostatic laminar shear flow, while forced SMAD6 expression rescued misalignment induced by reduced Notch1 signaling. SMAD6-dependent homeostatic laminar flow responses required the Notch ligand Dll4 and Notch transcriptional activity. Mechanistically, neither the N-terminal nor the C-terminal domain of SMAD6 alone rescued flow alignment upon loss of Notch signaling. Endothelial cells with reduced Smad6 levels had compromised barrier function, and RNA profiling revealed upregulation of proliferation-associated genes and down regulation of junction-associated genes. Among junction-related genes affected by SMAD6 levels, the proto-cadherin PCDH12 was upregulated by homeostatic flow and required for proper flow-mediated endothelial cell alignment. Thus, SMAD6 is a critical integrator of flow-mediated signaling inputs downstream of Notch1, as vessels transition from an angiogenic to a homeostatic phenotype.

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Excess centrosomes induce p53‐dependent senescence without DNA damage in endothelial cells

Cited by 9 publications

References 51 publications

Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway

Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway

Excess centrosomes disrupt vascular lumenization and endothelial cell adherens junctions

SMAD6 Integrates Endothelial Cell Homeostatic Flow Responses Downstream of Notch

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