Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PAK5-mediated AIF phosphorylation inhibits its nuclear translocation and promotes breast cancer tumorigenesis.

ABSTRACT: Although p21 activated kinase 5 (PAK5) is related to the progression of multiple cancers, its biological function in breast cancer remains unclear. Apoptosis-inducing factor (AIF) is a vital apoptosis factor in mitochondria, which can be released from mitochondria and enter the nucleus, causing caspase-independent apoptosis. In this study, we reveal that PAK5 inhibits apoptosis by preventing the nuclear translocation of AIF. PAK5 inhibits the release of AIF from mitochondria in breast cancer cells by decreasing the mitochondria membrane permeability and increasing the membrane potential. Furthermore, PAK5 phosphorylates AIF at Thr281 site to inhibit the formation of AIF/importin α3 complex, leading to decrease AIF nuclear translocation. Functionally, we demonstrate that PAK5-mediated AIF phosphorylation promotes the proliferation of breast cancer cells and accelerates the growth of breast cancer in vivo. Significantly, PAK5 and AIF expression in breast cancer are positively correlated with poor patient prognosis. PAK5 expression is negatively correlated with AIF nuclear translocation. These results suggest that PAK5-AIF signaling pathway may play an essential role in mammary tumorigenesis, providing a new therapeutic target for the treatment of breast cancer.

SUBMITTER: Xing Y

PROVIDER: S-EPMC8040471 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

COPI-Mediated Nuclear Translocation of EGFRvIII Promotes STAT3 Phosphorylation and PKM2 Nuclear Localization.

Project description:As a non-ligand-dependent activation protein, EGFRvIII is the most common mutant of EGFR, and its existence or especially its nuclear translocation in tumors can exacerbate the malignancy. Compared with the nuclear translocation of EGFR, which has been studied extensively, the specific mechanism by which EGFRvIII undergoes nuclear translocation has not yet been reported. Here, we found that EGFRvIII eventually reached the nucleus with the involvement of the Golgi and endoplasmic reticulum (ER) in glioma cells. In this process, syntaxin-6 was responsible for the identification and transport of EGFRvIII on Golgi. We also demonstrated that COPI mediated the reverse transport of EGFRvIII from the Golgi to ER, which process was also important for EGFRvIII's nuclear accumulation. EGFRvIII's nuclear translocation can significantly promote STAT3 phosphorylation and PKM2 nuclear localization. Finally, we showed that EGFRvIII's nuclear translocation obviously induced the growth of gliomas in an intracranial xenotransplantation experiment. These data suggested that searching methods that inhibit EGFRvIII entry into the nucleus will be effective glioma treatments.

| S-EPMC6329918 | biostudies-literature

EGF receptor-mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling.

Project description:Excessive accumulation of collagen leads to fibrosis. Integrin α1β1 (Itgα1β1) prevents kidney fibrosis by reducing collagen production through inhibition of the EGF receptor (EGFR) that phosphorylates cytoplasmic and nuclear proteins. To elucidate how the Itgα1β1/EGFR axis controls collagen synthesis, we analyzed the levels of nuclear tyrosine phosphorylated proteins in WT and Itgα1-null kidney cells. We show that the phosphorylation of the RNA-DNA binding protein fused in sarcoma (FUS) is higher in Itgα1-null cells. FUS contains EGFR-targeted phosphorylation sites and, in Itgα1-null cells, activated EGFR promotes FUS phosphorylation and nuclear translocation. Nuclear FUS binds to the collagen IV promoter, commencing gene transcription that is reduced by inhibiting EGFR, down-regulating FUS, or expressing FUS mutated in the EGFR-targeted phosphorylation sites. Finally, a cell-penetrating peptide that inhibits FUS nuclear translocation reduces FUS nuclear content and collagen IV transcription. Thus, EGFR-mediated FUS phosphorylation regulates FUS nuclear translocation and transcription of a major profibrotic collagen gene. Targeting FUS nuclear translocation offers a new antifibrotic therapy.

| S-EPMC7480104 | biostudies-literature

CDK2-activated TRIM32 phosphorylation and nuclear translocation promotes radioresistance in triple-negative breast cancer.

Project description:IntroductionDespite radiotherapy being one of the major treatments for triple-negative breast cancer (TNBC), new molecular targets for its treatment are still required due to radioresistance. CDK2 plays a critical role in TNBC. However, the mechanism by which CDK2 promotes TNBC radioresistance remains to be clearly elucidated.ObjectivesWe aimed to elucidate the relationship between CDK2 and TRIM32 and the regulation mechanism in TNBC.MethodsWe performed immunohistochemical staining to detect nuclear TRIM32, CDK2 and STAT3 on TNBC tissues. Western blot assays and PCR were used to detect the protein and mRNA level changes. CRISPR/Cas9 used to knock out CDK2. shRNA-knockdown and transfection assays also used to knock out target genes. GST pull-down analysis, immunoprecipitation (IP) assay and in vitro isomerization analysis also used. Tumorigenesis studies also used to verify the results in vitro.ResultsHerein, tripartite motif-containing protein 32 (TRIM32) is revealed as a substrate of CDK2. Radiotherapy promotes the binding of CDK2 and TRIM32, thus leading to increased CDK2-dependent phosphorylation of TRIM32 at serines 328 and 339. This causes the recruitment of PIN1, involved in cis-trans isomerization of TRIM32, resulting in importin α3 binding to TRIM32 and contributing to its nuclear translocation. Nuclear TRIM32 inhibits TC45-dephosphorylated STAT3, Leading to increased transcription of STAT3 and radioresistance in TNBC. These results were validated by clinical prognosis confirmed by the correlative expressions of the critical components of the CDK2/TRIM32/STAT3 signaling pathway.ConclusionsOur findings demonstrate that regulating the CDK2/TRIM32/STAT3 pathway is a promising strategy for reducing radioresistance in TNBC.

| S-EPMC11258662 | biostudies-literature

PAK1-mediated MORC2 phosphorylation promotes gastric tumorigenesis.

Project description:To date, microrchidia (MORC) family CW-type zinc-finger 2 (MORC2), has been found to be involved in p21-activated kinase1 (PAK1) pathway to maintain genomic integrity. Here, we explore its novel role in cancer. We demonstrate that PAK1-mediated MORC2 phosphorylation promotes cell cycle progression, defective phosphorylation of MORC2-S677A results in attenuated cell proliferation and tumorigenicity of gastric cancer cells, which is significantly enhanced in overexpression of phospho-mimic MORC2-S677E form, suggesting the importance of MORC2 phosphorylation in tumorigenesis. More importantly, phosphorylation of MORC2 correlates positively with PAK1 expression in clinical gastric cancer. Furthermore, high expression of PAK1 and phosphorylation of MORC2 appear to be associated with poor prognosis of clinical gastric cancer. Collectively, these findings revealed a novel function of MORC2 phosphorylation in promoting gastric cell proliferation in vitro and tumorigenesis in vivo, suggesting that blocking PAK1-mediated MORC2 phosphorylation might be a potential therapeutic strategy for gastric tumorigenesis.

| S-EPMC4496403 | biostudies-literature

YB-1 Phosphorylation at Serine 209 Inhibits Its Nuclear Translocation.

Project description:YB-1 is a multifunctional DNA- and RNA-binding protein involved in cell proliferation, differentiation, and migration. YB-1 is a predominantly cytoplasmic protein that is transported to the nucleus in certain conditions, including DNA-damaging stress, transcription inhibition, and viral infection. In tumors, YB-1 nuclear localization correlates with high aggressiveness, multidrug resistance, and a poor prognosis. It is known that posttranslational modifications can regulate the nuclear translocation of YB-1. In particular, well-studied phosphorylation at serine 102 (S102) activates YB-1 nuclear import. Here, we report that Akt kinase phosphorylates YB-1 in vitro at serine 209 (S209), which is located in the vicinity of the YB-1 nuclear localization signal. Using phosphomimetic substitutions, we showed that S209 phosphorylation inhibits YB-1 nuclear translocation and prevents p-S102-mediated YB-1 nuclear import.

| S-EPMC8745666 | biostudies-literature

A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation.

Project description:Circular RNAs (circRNAs) are a subclass of noncoding RNAs widely expressed in mammalian cells. We report here the tumorigenic capacity of a circRNA derived from angiomotin-like1 (circ-Amotl1). Circ-Amotl1 is highly expressed in patient tumor samples and cancer cell lines. Single-cell inoculations using circ-Amotl1-transfected tumor cells showed a 30-fold increase in proliferative capacity relative to control. Agarose colony-formation assays similarly revealed a 142-fold increase. Tumor-take rate in nude mouse xenografts using 6-day (219 cells) and 3-day (9 cells) colonies were 100%, suggesting tumor-forming potential of every cell. Subcutaneous single-cell injections led to the formation of palpable tumors in 41% of mice, with tumor sizes >1 cm3 in 1 month. We further found that this potent tumorigenicity was triggered through interactions between circ-Amotl1 and c-myc. A putative binding site was identified in silico and tested experimentally. Ectopic expression of circ-Amotl1 increased retention of nuclear c-myc, appearing to promote c-myc stability and upregulate c-myc targets. Expression of circ-Amotl1 also increased the affinity of c-myc binding to a number of promoters. Our study therefore reveals a novel function of circRNAs in tumorigenesis, and this subclass of noncoding RNAs may represent a potential target in cancer therapy.

| S-EPMC5563992 | biostudies-literature

Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer.

Project description:PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110α, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85β disassociates from p110α helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85β recruits deubiquitinase USP7 to stabilize EZH1 and EZH2 and enhances H3K27 trimethylation. Knockout of p85β or p85β NLS mutant reduces the growth of tumors harboring a PIK3CA helical domain mutation. Our studies illuminate a novel mechanism by which PIK3CA helical domain mutations exert their oncogenic function. Finally, a combination of Alpelisib, a p110α-specific inhibitor, and an EZH inhibitor, Tazemetostat, induces regression of xenograft tumors harboring a PIK3CA helical domain mutation, but not tumors with either a WT PIK3CA or a PIK3CA kinase domain mutation, suggesting that the drug combination could be an effective therapeutic approach for PIK3CA helical domain mutant tumors.

| S-EPMC9007954 | biostudies-literature

CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis.

Project description:BackgroundCDK5, an atypical member of the CDK family, play a significant role in the tumorigenesis of multiple organ, but CDK5 and its substrates in genesis and development of HCC is still unclear.MethodsExpression of CDK5 in HCC tumor and paired adjacent noncancerous tissues from 90 patients were measured by Western blotting, immunohistochemistry, and real-time PCR. The role of CDK5 in cell function and tumorigenesis was explored in HCC cell lines, ex vivo xenografts and diethylnitrosamine induced HCC model. Furthermore, comparative phosphoproteomic screening identified the oncoprotein TPX2 as a new substrate of CDK5. We also identified the effect of CDK5/P25 interaction blocker tamoxifen on HCC cell growth and migration.ResultsCDK5 was increased in HCC tisues and the level of CDK5 was correlated with the severity of HCC based on patient recurrence and 5-year fatality rate. Exogenously expressed CDK5 but not kinase-dead CDK5 promoted proliferation, migration, and invasion of HCC cells. Functional ablation of CDK5 significantly inhibited the exacerbation of HCC cells. Xenograft implantation of HCC cells overexpressing CDK5 promoted tumorigenesis, and genetic knockdown of CDK5 reduced HCC growth and metastasis in vivo. More importantly, heterozygous knockout CDK5 (Cdk5+/-) attenuated HCC tumorigenesis induced by diethylnitrosamine. CDK5-mediated phosphorylation of TPX2 at serine 486 promoted its protein stability. TPX2 silence could restore HCC cell migration capability with overexpression CDK5. Treatment with tamoxifen inhibited cell growth and migration of HCC, demonstrating the role of active CDK5 in HCC.ConclusionsOur results suggest activation of CDK5 is associated with HCC tumorigenesis. CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular proliferation and tumorigenicity.

| S-EPMC6610961 | biostudies-literature

Nuclear PD-L1 promotes EGR1-mediated angiogenesis and accelerates tumorigenesis.

Project description:Targeting programmed cell death protein ligand 1 (PD-L1) remains one of the most essential immunotherapies in cancer1,2. PD-L1 has been detected in the nucleus in multiple malignancies, playing an oncogenic role independent of immune checkpoint regulation3-5. Howbeit, the regulatory function of nuclear PD-L1 (nPD-L1) remains to be fully understood. Here, we report that nPD-L1 is an endogenous accelerator for cancer angiogenesis. First, we found that an abundant proportion of PD-L1 was distributed within the nucleus of uveal melanoma samples, which is associated with an unfavorable outcome. Moreover, the capacity of promoting angiogenesis was largely attenuated in the nPD-L1-deficient cells both in vivo and in vitro. Mechanistically, nPD-L1 facilitates p-STAT3 binding to the promoter of early growth response-1 (EGR1), resulting in the activation of EGR1-mediated angiogenesis. Therapeutically, the inhibition of histone deacetylase 2 restores the normal acetylation level of PD-L1, blocking its nuclear translocation and thereby attenuating tumor angiogenesis. Conclusively, we reveal that nPD-L1 promotes angiogenesis in malignancies, and provide a novel anti-vascularization strategy through blocking aberrant PD-L1 nuclear translocation for tumor therapy.

| S-EPMC10050073 | biostudies-literature

Dimethyl celecoxib sensitizes gastric cancer cells to ABT-737 via AIF nuclear translocation.

Project description:Gastric cancer is the fourth most common cancer in the world. The clinical applications of both chemotherapy and targeted drugs are limited because of the complexity of gastric cancer. In this study, sulforhodamine B, colony formation assay, 4',6-diamidino-2-phenylindole (DAPI) stain, flow cytometry were used to determine the in vitro cytotoxicity, apoptosis and mitochondrial membrane potential of gastric cancer AGS and HGC-27 cells before and after treatment. Real-time PCR and Western blot were used to analyse the mRNA transcription and protein expression respectively. Confocal microscopy was used to determine the localization of target protein within the cells. Treatment with the combination of ABT-737 and 2,5-dimethyl-celecoxib (DMC) showed strong synergistic effect in both AGS and HGC-27 cells. Moreover, DMC would not influence the intracellular prostaglandin E2 (PGE2) level, thus lacking the toxicity profile of celecoxib. Interestingly, given the significant synergistic effect, combination treatment did not affect the protein expression of BH-3 proteins including Puma, Noxa and Bim. In combination treatment, cell apoptosis was found independent of caspase-3 activation. The translocation of apoptosis-inducing factor (AIF) from mitochondrion to nuclear was responsible for the induced apoptosis in the combination treatment. Taken together, this study provided a novel combination treatment regimen for gastric cancer. Furthermore, the existence of caspase-independent apoptotic pathway induced by treatment of ABT-737 was not yet seen until combined with DMC, which shed light on an alternative mechanism involved in Bcl-2 inhibitor-induced apoptosis.

| S-EPMC5082400 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data