A p53–phosphoinositide signalosome regulates nuclear AKT activation

Chen, Mo; Choi, Sungyeol; Wen, Tianmu; Chen, Changliang; Thapa, Narendra; Lee, Jeong Hyo; Cryns, Vincent L.; Anderson, Richard A.

doi:10.1038/s41556-022-00949-1

Cited by 44 publications

(73 citation statements)

References 73 publications

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“…The phosphatase-inactivating mutation of PTEN, such as G129R and C124S, enhances the ability of PTEN nuclear import in response to IR [ 34 ]. Another study also confirmed that PTEN knockdown increases nuclear p-Akt [ 69 ], which may indicate that the reduction in nuclear PTEN increases DNA repair and leads to p-Akt nuclear transport. However, the interconnected determination of nuclear import by mono- or poly-ubiquitylation modification is still unclear.…”

Section: Discussionmentioning

confidence: 71%

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Dong

Liu

et al. 2022

Cells

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The tumor suppressor PTEN mainly inhibits the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus. The status of PTEN remains therapeutic effectiveness for chemoresistance of the DNA alkylating agent temozolomide (TMZ) in glioblastoma (GB). However, the underlying mechanisms of PTEN’s interconnected role in the cytoplasm and nucleus in TMZ resistance are still unclear. In this study, we report that TMZ−induced PTEN nuclear import depends on PTEN ubiquitylation modification by Smurf1. The Smurf1 suppression decreases the TMZ−induced PTEN nuclear translocation and enhances the DNA damage. In addition, Smurf1 degrades cytoplasmic PTEN K289E (the nuclear−import−deficient PTEN mutant) to activate the PI3K/Akt pathway under TMZ treatment. Altogether, Smurf1 interconnectedly promotes PTEN nuclear function (DNA repair) and cytoplasmic function (activation of PI3K/Akt pathway) to resist TMZ. These results provide a proof−of−concept demonstration for a potential strategy to overcome the TMZ resistance in PTEN wild−type GB patients by targeting Smurf1.

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Section: Discussionmentioning

confidence: 71%

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Dong

Liu

et al. 2022

Cells

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“…RNA-seq results indicated that the P53 downstream pathway was significantly enriched in the differentially expressed genes contained in Part II ( Figure S4C ). Mutations in P53 have been reported leading to the activation of AKT/VEGFR signal cascade in some cancers [ 28 , 29 ]. We found the protein expression level of the VEGFR signal pathway suppressed in normal esophageal epithelial cells after long-term exposure to ABS or BS treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Vascular endothelial growth factor ( VEGF ) can stimulate the proliferation of endothelial cells by interacting with VEGFR , which plays a vital role in tumor proliferation and metastasis [ 38 , 39 ]. P53 mutants showed activation of AKT/VEGFR signal cascade [ 28 , 40 ]. Our study showed that prolonged exposure to bile acid treatment downregulated the phosphorylation of AKT and expression of VEGFR in P53 -proficient esophagus epithelial cells ( Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

P53 Deficiency Accelerate Esophageal Epithelium Intestinal Metaplasia Malignancy

Qiu

Guo

et al. 2023

Biomedicines

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Barrett’s esophagus (BE) is a precancerous lesion of esophageal adenocarcinoma (EAC). It is a pathological change in which the squamous epithelium distal esophagus is replaced by columnar epithelium. Loss of P53 is involved in the development of BE and is taken as a risk factor for the progression. We established a HET1A cell line with P53 stably knockdown by adenovirus vector infection, followed by 30 days of successive acidic bile salt treatment. MTT, transwell assay, and wound closure assay were applied to assess cell proliferation and migration ability. The expression of key factors was analyzed by RT-qPCR, western blotting and immunohistochemical staining. Our data show that the protein expression level of P53 reduced after exposure to acidic bile salt treatment, and the P53 deficiency favors the survival of esophageal epithelial cells to accommodate the stimulation of acidic bile salts. Furthermore, exposure to acidic bile salt decreases cell adhesions by repressing the JAK/STAT signaling pathway and activating VEGFR/AKT in P53-deficient esophageal cells. In EAC clinical samples, P53 protein expression is positively correlated with that of ICAM1 and STAT3 and negatively correlated with VEGFR protein expression levels. These findings elucidate the role of P53 in the formation of BE, explain the mechanism of P53 deficiency as a higher risk of progression for BE formation, and provide potential therapeutic targets for EAC.

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“…The genes that have been differentially modulated are associated with pathways, including p53 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, Hippo signaling pathway, TNF signaling pathway, chemokine ligand 12 signaling pathway, and cytokine production; moreover, retinol metabolism, carbon metabolism, glycolysis, gluconeogenesis, and primary bile acid biosynthesis related with cancer also changed in the two clusters. Previous studies had showed that p53 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway are important pathways involved in tumor development and metastasis ( 22 , 23 ). Additionally, glycolysis, gluconeogenesis, and bile acid biosynthesis also play an important role in the tumor progression ( 24 – 26 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

et al. 2022

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Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.

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A p53–phosphoinositide signalosome regulates nuclear AKT activation

Cited by 44 publications

References 73 publications

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

P53 Deficiency Accelerate Esophageal Epithelium Intestinal Metaplasia Malignancy

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

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