p53 regulates cytoskeleton remodeling to suppress tumor progression

Araki, Keigo; Ebata, Takahiro; Guo, Alvin Kunyao; Tobiume, Kei; Wolf, Steven John; Kawauchi, Keiko

doi:10.1007/s00018-015-1989-9

Cited by 32 publications

(28 citation statements)

References 200 publications

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“…p53 alters cell behavior through remodeling of the actin cytoskeleton [ 49 ], and actin remodeling is involved in the determination of cell fate upon doxorubicin treatment [ 17 , 19 – 22 , 50 ]. While actin remodeling plays a central role in the morphological changes of cells [ 51 ], we noticed that the spheroids that formed on the 2 kPa substrate spread out with thin protrusions after treatment with doxorubicin (Figures 4(a) – 4(c) ).…”

Section: Resultsmentioning

confidence: 99%

Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression

Ebata

Mitsui

Sugimoto

et al. 2017

BioMed Research International

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The physical properties of the extracellular matrix (ECM), such as stiffness, are involved in the determination of the characteristics of cancer cells, including chemotherapy sensitivity. Resistance to chemotherapy is often linked to dysfunction of tumor suppressor p53; however, it remains elusive whether the ECM microenvironment interferes with p53 activation in cancer cells. Here, we show that, in MCF-7 breast cancer cells, extracellular stiffness influences p53 activation induced by the antitumor drug doxorubicin. Cell growth inhibition by doxorubicin was increased in response to ECM rigidity in a p53-dependent manner. The expression of Rho-associated coiled coil-containing protein kinase (ROCK) 2, which induces the activation of myosin II, was significantly higher when cells were cultured on stiffer ECM substrates. Knockdown of ROCK2 expression or pharmacological inhibition of ROCK decreased doxorubicin-induced p53 activation. Our results suggest that a soft ECM causes downregulation of ROCK2 expression, which drives resistance to chemotherapy by repressing p53 activation.

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Section: Resultsmentioning

confidence: 99%

Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression

Ebata

Mitsui

Sugimoto

et al. 2017

BioMed Research International

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“…Lamellipodia, filopodia, and invadopodia can remodel the cytoskeleton by changing microfilaments, microtubules, and intermediate filaments. In the process of tumor cell migration, cytoskeletal reorganization is regulated by non-coding RNA and signaling pathways [ 48 , 49 ] (Fig. 1 ).…”

Section: Cytoskeletal Reorganization and Cancer Cell Movementmentioning

confidence: 99%

LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis

et al. 2018

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Some of the key steps in cancer metastasis are the migration and invasion of tumor cells; these processes require rearrangement of the cytoskeleton. Actin filaments, microtubules, and intermediate filaments involved in the formation of cytoskeletal structures, such as stress fibers and pseudopodia, promote the invasion and metastasis of tumor cells. Therefore, it is important to explore the mechanisms underlying cytoskeletal regulation. The ras homolog family (Rho) and Rho-associated coiled-coil containing protein serine/threonine kinase (ROCK) signaling pathway is involved in the regulation of the cytoskeleton. Moreover, long noncoding RNAs (lncRNAs) have essential roles in tumor migration and guide gene regulation during cancer progression. LncRNAs can regulate the cytoskeleton directly or may influence the cytoskeleton via Rho/ROCK signaling during tumor migration. In this review, we focus on the regulatory association between lncRNAs and the cytoskeleton and discuss the pathways and mechanisms involved in the regulation of cancer metastasis.

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“…Interestingly, the process of p53 trafficking is associated with cytoskeletal proteins including actin and microtubules. Some studies show that wild type p53 induces reorganization of the actin cytoskeleton and modulates various cytoskeleton associated proteins 16 , 17 . Other studies indicate that p53 trafficking is regulated by actin, microtubules, and other cytoskeletal proteins 18 – 21 .…”

Section: Introductionmentioning

confidence: 99%

Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation

Liu

Wang

LePochat

et al. 2017

Sci Rep

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Amyloid β (Aβ) accumulation is an early event in the pathogenesis of Alzheimer’s disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Aβ deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Aβ-induced mitochondrial and synaptic dysfunction. In this study, we show that activated cofilin (S3A) preferentially forms a complex with p53 and promotes its mitochondrial and nuclear localization, resulting in transcription of p53-responsive genes and promotion of apoptosis. Conversely, reduction of endogenous cofilin by knockdown or genetic deficiency inhibits mitochondrial and nuclear translocation of p53 in cultured cells and in APP/PS1 mice. This cofilin-p53 pro-apoptotic pathway is subject to negative regulation by PLD1 thorough cofilin inactivation and inhibition of cofilin/p53 complex formation. Finally, activated cofilin is unable to induce apoptosis in cells genetically lacking p53. These findings taken together indicate that cofilin coopts and requires the nuclear and mitochondrial pro-apoptotic p53 program to induce and execute apoptosis, while PLD1 functions in a regulatory multi-brake capacity in this pathway.

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p53 regulates cytoskeleton remodeling to suppress tumor progression

Cited by 32 publications

References 200 publications

Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression

Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression

LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis

Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation

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