Nuclear Nestin deficiency drives tumor senescence via lamin A/C-dependent nuclear deformation

Zhang, Yanan; Wang, Jiancheng; Huang, Weijun; Cai, Jianye; Ba, Junhui; Wang, Yi; Qin, Ke; Huang, Yinong; Liu, Xin; Qiu, Yuan; Lu, Qiping; Sui, Xin; Shi, Yue; Wang, Tao; Shen, Huiyong; Guan, Yuanjun; Zhou, Ying; Chen, Yuan; Wang, Maosheng; Xiang, Andy Peng

doi:10.1038/s41467-018-05808-y

Cited by 45 publications

(42 citation statements)

References 60 publications

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“…These BrdU-positive cells were Nestin- and GFAP-positive (Figure 9C ), but Iba1-negative (Figure S4 ), suggesting that they are a lineage of NPCs but not microglial cells. We noticed that Nestin proteins were highly concentrated in the nuclei of BrdU-positive cells (Figure 9C ), consistent with a recent report indicating that nuclear Nestin is involved in preventing cell senescence (Zhang et al, 2018 ). These data suggest that RNase A-induced NPCs are able to migrate to various brain regions and they further support the role of RNase A in promoting NPC proliferation and maintenance.…”

Section: Resultssupporting

confidence: 92%

RNase A Promotes Proliferation of Neuronal Progenitor Cells via an ERK-Dependent Pathway

Liu

Chen

Hung

et al. 2018

Front. Mol. Neurosci.

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Members of the ribonuclease A (RNase A) superfamily regulate various physiological processes. RNase A, the best-studied member of the RNase A superfamily, is widely expressed in different tissues, including brains. We unexpectedly found that RNase A can trigger proliferation of neuronal progenitor cells (NPC) both in vitro and in vivo. RNase A treatment induced cell proliferation in dissociated neuronal cultures and increased cell mass in neurosphere cultures. BrdU (5-Bromo-2'-Deoxyuridine) labeling confirmed the effect of RNase A on cell proliferation. Those dividing cells were Nestin- and SOX2-positive, suggesting that RNase A triggers NPC proliferation. The proliferation inhibitor Ara-C completely suppressed the effect of RNase A on NPC counts, further supporting that RNase A increases NPC number mainly by promoting proliferation. Moreover, we found that RNase A treatment increased ERK phosphorylation and blockade of the ERK pathway inhibited the effect of RNase A on NPC proliferation. Intracerebroventricular injection of RNase A into mouse brain increased the population of 5-ethynyl-2'-deoxyuridine (EdU) or BrdU-labeled cells in the subventricular zone. Those RNase A-induced NPCs were able to migrate into other brain areas, including hippocampus, amygdala, cortex, striatum, and thalamus. In conclusion, our study shows that RNase A promotes proliferation of NPCs via an ERK-dependent pathway and further diversifies the physiological functions of the RNase A family.

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Section: Resultssupporting

confidence: 92%

RNase A Promotes Proliferation of Neuronal Progenitor Cells via an ERK-Dependent Pathway

Liu

Chen

Hung

et al. 2018

Front. Mol. Neurosci.

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“…Mutant LMNA, mutations that affect lamin A/C expression, and lamin A/C depletion in cells have been associated with premature aging and cellular senescence (8, 30, 32, 42, 45). Based on the concurrent lamin A/C downregulation and nuclear deformity observed in lung cancer cells exposed to PF-573228 (Figures 3A,B), we examined the development of cellular senescence in lung cancer cells treated with PF-573228.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, nuclear lobulation and distorted nuclear morphology have been reported in cells with the LNMA mutation or lamin A/C downregulation (41–43). The LNMA mutation or lamin A/C downregulation has been shown to result in nuclear distortion with a pathogenic tendency to develop aging and senescence (8, 30, 42, 57). The nuclear deformity in PF-573228-treated lung cancer cells (Figures 2B, 3A–C) supports a pathophysiological impact from the inactivation of FAK signaling to downregulate lamin A/C.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of FAK Signaling Elicits Lamin A/C-Associated Nuclear Deformity and Cellular Senescence

et al. 2019

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Focal adhesion kinase (FAK) is a non-receptor kinase that facilitates tumor aggressiveness. The effects of FAK inhibition include arresting proliferation, limiting metastasis, and inhibiting angiogenesis. PF-573228 is an ATP-competitive inhibitor of FAK. Treating lung cancer cells with PF-573228 resulted in FAK inactivation and changes in the expressions of lamin A/C and nuclear deformity. Since lamin A/C downregulation or deficiency was associated with cellular senescence, the senescence-associated β-galactosidase (SA-β-gal) assay was used to investigate whether PF-573228 treatment drove cellular senescence, which showed more SA-β-gal-positive cells in culture. p53 is known to play a pivotal role in mediating the progression of cellular senescence, and the PF-573228-treated lung cancer cells resulted in a higher p53 expression level. Subsequently, the FAK depletion in lung cancer cells was employed to confirm the role of FAK inhibition on cellular senescence. FAK depletion and pharmacological inhibition of lung cancer cells elicited similar patterns of cellular senescence, lamin A/C downregulation, and p53 upregulation, implying that FAK signaling is associated with the expression of p53 and the maintenance of lamin A/C levels to shape regular nuclear morphology and manage anti-senescence. Conversely, FAK inactivation led to p53 upregulation, disorganization of the nuclear matrix, and consequently cellular senescence. Our data suggest a new FAK signaling pathway, in that abolishing FAK signaling can activate the senescence program in cells. Triggering cellular senescence could be a new therapeutic approach to limit tumor growth.

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“…However, the effect of nestin depletion on cdk5 activity (promoting or inhibiting) has varied between reports and assay systems and has been a point of contention Lindqvist et al, 2017;Sahlgren et al, 2006;J. Wang et al, 2017;Yang et al, 2011;Zhang et al, 2018). Since the relevant endogenous cdk5 substrate in myoblasts remains unknown, exogenous substrates (such as recombinant H1 histone protein) are commonly used for phosphorylation assays.…”

Section: Discussionmentioning

confidence: 99%

Nestin selectively facilitates the phosphorylation of the Lissencephaly-linked protein doublecortin (DCX) by cdk5/p35 to regulate growth cone morphology and Sema3a sensitivity in developing neurons

Bott

Keil

McMahon

et al. 2019

Preprint

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AbstractNestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Lastly, we use cortical cultures derived from DCX knockout mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.Significance StatementNestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.

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Nuclear Nestin deficiency drives tumor senescence via lamin A/C-dependent nuclear deformation

Cited by 45 publications

References 60 publications

RNase A Promotes Proliferation of Neuronal Progenitor Cells via an ERK-Dependent Pathway

RNase A Promotes Proliferation of Neuronal Progenitor Cells via an ERK-Dependent Pathway

Inhibition of FAK Signaling Elicits Lamin A/C-Associated Nuclear Deformity and Cellular Senescence

Nestin selectively facilitates the phosphorylation of the Lissencephaly-linked protein doublecortin (DCX) by cdk5/p35 to regulate growth cone morphology and Sema3a sensitivity in developing neurons

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