scholarly journals SUMOylation is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

2020 ◽  
Author(s):  
Tatiana Erazo ◽  
Sergio Espinosa-Gil ◽  
Nora Diéguez-Martínez ◽  
Néstor Gómez ◽  
Jose M. Lizcano
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Nuclear Localization ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Kinase Domain ◽  
Cancer Cell Proliferation ◽  
Transcriptional Activation Domain ◽  
Nuclear Shuttling

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses, and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol, and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or Cdc37 overexpression -mechanisms that induce nuclear ERK5- induced ERK5 SUMO-2 modification at residues Lys6/Lys22 in cancer cells. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to EGF stimulation. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of transcription.

scholarly journals SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

2020 ◽  
Vol 21 (6) ◽  
pp. 2203 ◽  
Author(s):  
Tatiana Erazo ◽  
Sergio Espinosa-Gil ◽  
Nora Diéguez-Martínez ◽  
Néstor Gómez ◽  
Jose M Lizcano
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Nuclear Localization ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Kinase Domain ◽  
Cancer Cell Proliferation ◽  
Transcriptional Activation Domain ◽  
Nuclear Shuttling

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37—mechanisms that increase nuclear ERK5—induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription.

scholarly journals Emodin and Aloe-Emodin Suppress Breast Cancer Cell Proliferation through ERαInhibition

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Pao-Hsuan Huang ◽  
Chih-Yang Huang ◽  
Mei-Chih Chen ◽  
Yueh-Tsung Lee ◽  
Chia-Herng Yue ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Estrogenic Activity ◽  
Cancer Cell Proliferation ◽  
Breast Cancer Cell Proliferation ◽  
Aloe Emodin

The anthraquinones emodin and aloe-emodin are abundant in rhubarb. Several lines of evidence indicate that emodin and aloe-emodin have estrogenic activity as phytoestrogens. However, their effects on estrogen receptorα(ERα) activation and breast cancer cell growth remain controversial. The goal of this study is to investigate the effects and molecular mechanisms of emodin and aloe-emodin on breast cancer cell proliferation. Our results indicate that both emodin and aloe-emodin are capable of inhibiting breast cancer cell proliferation by downregulating ERαprotein levels, thereby suppressing ERαtranscriptional activation. Furthermore, aloe-emodin treatment led to the dissociation of heat shock protein 90 (HSP90) and ERαand increased ERαubiquitination. Although emodin had similar effects to aloe-emodin, it was not capable of promoting HSP90/ERαdissociation and ERαubiquitination. Protein fractionation results suggest that aloe-emodin tended to induce cytosolic ERαdegradation. Although emodin might induce cytosolic ERαdegradation, it primarily affected nuclear ERαdistribution similar to the action of estrogen when protein degradation was blocked. In conclusion, our data demonstrate that emodin and aloe-emodin specifically suppress breast cancer cell proliferation by targeting ERαprotein stability through distinct mechanisms. These findings suggest a possible application of anthraquinones in preventing or treating breast cancer in the future.

scholarly journals MICAL2 Contributes to Gastric Cancer Cell Proliferation by Promoting YAP Dephosphorylation and Nuclear Translocation

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Chenxiang Qi ◽  
Pengxiang Min ◽  
Qianwen Wang ◽  
Yueyuan Wang ◽  
Yixuan Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Gastric Cancer Cell ◽  
Nuclear Translocation ◽  
S Phase ◽  
Ros Generation ◽  
Cancer Cell Proliferation ◽  
Poor Overall Survival ◽  
Gastric Cancer Cell Proliferation

Dynamic cytoskeletal rearrangements underlie the changes that occur during cell division in proliferating cells. MICAL2 has been reported to possess reactive oxygen species- (ROS-) generating properties and act as an important regulator of cytoskeletal dynamics. However, whether it plays a role in gastric cancer cell proliferation is not known. In the present study, we found that MICAL2 was highly expressed in gastric cancer tissues, and this high expression level was associated with carcinogenesis and poor overall survival in gastric cancer patients. The knockdown of MICAL2 led to cell cycle arrest in the S phase and attenuated cell proliferation. Concomitant with S-phase arrest, a decrease in CDK6 and cyclin D protein levels was observed. Furthermore, MICAL2 knockdown attenuated intracellular ROS generation, while MICAL2 overexpression led to a decrease in the p-YAP/YAP ratio and promoted YAP nuclear localization and cell proliferation, effects that were reversed by pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) and SOD-mimetic drug tempol. We further found that MICAL2 induced Cdc42 activation, and activated Cdc42 mediated the effect of MICAL2 on YAP dephosphorylation and nuclear translocation. Collectively, our results showed that MICAL2 has a promotive effect on gastric cancer cell proliferation through ROS generation and Cdc42 activation, both of which independently contribute to YAP dephosphorylation and its nuclear translocation.

Heregulin β1 promotes breast cancer cell proliferation through Rac/ERK-dependent induction of cyclin D1 and p21Cip1

2008 ◽  
Vol 410 (1) ◽  
pp. 167-175 ◽  
Author(s):  
Chengfeng Yang ◽  
Eric A. Klein ◽  
Richard K. Assoian ◽  
Marcelo G. Kazanietz
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cyclin D1 ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Molecular Mechanisms ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Cancer Cell Proliferation ◽  
Breast Cancer Cell Proliferation

Accumulating evidence indicates that heregulins, EGF (epidermal growth factor)-like ligands, promote breast cancer cell proliferation and are involved in the progression of breast cancer towards an aggressive and invasive phenotype. However, there is limited information regarding the molecular mechanisms that mediate these effects. We have recently established that HRG (heregulin β1) promotes breast cancer cell proliferation and migration via cross-talk with EGFR (EGF receptor) that involves the activation of the small GTPase Rac1. In the present paper we report that Rac1 is an essential player for mediating the induction of cyclin D1 and p21Cip1 by HRG in breast cancer cells. Inhibition of Rac function by expressing either the Rac-GAP (GTPase-activating protein) β2-chimaerin or the dominant-negative Rac mutant N17Rac1, or Rac1 depletion using RNAi (RNA interference), abolished the cyclin D1 and p21Cip1 induction by HRG. Interestingly, the proliferative effect of HRG was impaired not only when the expression of Rac1 or cyclin D1 was inhibited, but also when cells were depleted of p21Cip1 using RNAi. Inhibition of EGFR, PI3K (phosphoinositide 3-kinase; kinases required for Rac activation by HRG) or MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] also blocked the up-regulation of cyclin D1 and p21Cip1 by HRG. In addition, we found that HRG activates NF-κB (nuclear factor κB) in a Rac1- and MEK-dependent fashion, and inhibition of NF-κB abrogates cyclin D1/p21Cip1 induction and proliferation by HRG. Taken together, these findings establish a central role for Rac1 in the control of HRG-induced breast cancer cell-cycle progression and proliferation through up-regulating the expression of cyclin D1 and p21Cip1.

scholarly journals USP15 and USP4 facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Tanuza Das ◽  
Eun-Young Lee ◽  
Hye Jin You ◽  
Eunice EunKyeong Kim ◽  
Eun Joo Song
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Alternative Splicing ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Cell Phenotype ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Endogenous Expression ◽  
Depletion Effect

AbstractThe deubiquitinating enzyme USP15 is implicated in several human cancers by regulating different cellular processes, including splicing regulation. However, the underlying molecular mechanisms of its functional relevance and the successive roles in enhanced tumorigenesis remain ambiguous. Here, we found that USP15 and its close paralog USP4 are overexpressed and facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1. Depletion of USP15 and USP4 impair SRSF1 splicing characterized by the replacement of exon 4 with non-coding intron sequences retained at its C-terminus, resulting in an alternative isoform SRSF1-3. We observed an increased endogenous expression of SRSF1 in lung cancer cells as well, and its overexpression significantly enhanced cancer cell phenotype and rescued the depletion effect of USP15 and USP4. However, the alternatively spliced isoform SRSF1-3 was deficient in such aspects for its premature degradation through nonsense-mediated mRNA decay. The increased USP15 expression contributes to the lung adenocarcinoma (LUAD) development and shows significantly lower disease-specific survival of patients with USP15 alteration. In short, we identified USP15 and USP4 as key regulators of SRSF1 alternative splicing with altered functions, which may represent the novel prognostic biomarker as well as a potential target for LUAD.

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