Role of TSC1 in physiology and diseases

Mallela, Karthik; Kumar, Arun

doi:10.1007/s11010-021-04088-3

Cited by 29 publications

(17 citation statements)

References 143 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AKT activation induces tuberous sclerosis protein 2 (TSC2) inhibition [ 118 ] and disrupt its interaction with TSC1 [ 119 ]. TSC1 is involved in cell growth and proliferation, survival, and autophagy [ 120 ]. Once activated, AKT induces protein synthesis and cell growth by mTOR activation and TSC1 and TSC2 inhibition [ 121 ].…”

Section: Pi3k/akt/mtor and Pancreatic Cancermentioning

confidence: 99%

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

Stanciu¹,

Ioniţă-Radu²,

Ştefani³

et al. 2022

IJMS

View full text Add to dashboard Cite

Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.

show abstract

Section: Pi3k/akt/mtor and Pancreatic Cancermentioning

confidence: 99%

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

Stanciu¹,

Ioniţă-Radu²,

Ştefani³

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…TSC1 and TSC2 form a GTPase-activating protein complex that inhibits RHEB, a crucial activator of mTORC1 signalling [ 29 ]. Inactivating TSC1 mutations are associated with tumour formation due to mTORC1 overactivity [ 36 ]. Silencing of TSC1 expression by CBX2 could therefore have similar oncogenic properties.…”

Section: Discussionmentioning

confidence: 99%

The Epigenetic Regulatory Protein CBX2 Promotes mTORC1 Signalling and Inhibits DREAM Complex Activity to Drive Breast Cancer Cell Growth

Bilton

Warren

Humphries

et al. 2022

Cancers

View full text Add to dashboard Cite

Chromobox 2 (CBX2) is a chromatin-binding component of polycomb repressive complex 1, which causes gene silencing. CBX2 expression is elevated in triple-negative breast cancer (TNBC), for which there are few therapeutic options. Here, we aimed to investigate the functional role of CBX2 in TNBC. CBX2 knockdown in TNBC models reduced cell numbers, which was rescued by ectopic expression of wild-type CBX2 but not a chromatin binding-deficient mutant. Blocking CBX2 chromatin interactions using the inhibitor SW2_152F also reduced cell growth, suggesting CBX2 chromatin binding is crucial for TNBC progression. RNA sequencing and gene set enrichment analysis of CBX2-depleted cells identified downregulation of oncogenic signalling pathways, including mTORC1 and E2F signalling. Subsequent analysis identified that CBX2 represses the expression of mTORC1 inhibitors and the tumour suppressor RBL2. RBL2 repression, in turn, inhibits DREAM complex activity. The DREAM complex inhibits E2F signalling, causing cell senescence; therefore, inhibition of the DREAM complex via CBX2 may be a key oncogenic driver. We observed similar effects in oestrogen receptor-positive breast cancer, and analysis of patient datasets suggested CBX2 inhibits RBL2 activity in other cancer types. Therapeutic inhibition of CBX2 could therefore repress mTORC1 activation and promote DREAM complex-mediated senescence in TNBC and could have similar effects in other cancer types.

show abstract

“…TSC1/TSC2 tumor suppressor complex can be used as an inhibitor of mTOR pathway. The destruction of TSC1/TSC2 tumor suppressor function may contribute to the occurrence of tumor [ 35 ]. It is reported that low TSC1 expression level is associated with poor clinical outcomes of breast cancer [ 36 ] and gastric cancer [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Study on the Expression Profile of Autophagy-Related Genes in Colon Adenocarcinoma

Hou

2022

Computational and Mathematical Methods in Medicine

View full text Add to dashboard Cite

Colon adenocarcinoma (COAD) is a common digestive tract tumor. Autophagy-related genes (ARGs) may play an obbligato role in the biological processes of COAD. This study was aimed at exploring the role of ARGs in COAD. Clinical data and RNA sequencing data of tumor and healthy samples were obtained from The Cancer Genome Atlas (TCGA), and discrepantly expressed ARGs were screened. Statistical differences of ARGs were performed with Gene Ontology (GO) functional annotation and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Eight ARGs were selected by univariate Cox and multivariate Cox regression. Kaplan–Meier (K-M) and multivariate receiver operating characteristic (multi-ROC) were used to check the fitness of the model. Among 398 COAD samples and 39 normal samples obtained from the TCGA database, 37 differentially expressed ARGs were screened. In the training group, eight prognostics-related ARGs (MTMR14, VAMP3, HSPA8, TSC1, DAPK1, CX3CL1, ATG13, and MAP1LC3C) were identified by Cox regression. A gene signature risk prediction model was constructed base on 8 autophagy-related genes. The survival time of the low-risk group was longer than the high-risk group, and the AUC of the model was 0.794. Univariate and multivariate Cox regression analysis showed that age and riskscore were the independent predictor. In conclusion, the prognosis model we built based one ARGs of COAD patients can estimate the prognosis of patients in clinical treatment.

show abstract

Role of TSC1 in physiology and diseases

Cited by 29 publications

References 143 publications

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

The Epigenetic Regulatory Protein CBX2 Promotes mTORC1 Signalling and Inhibits DREAM Complex Activity to Drive Breast Cancer Cell Growth

Study on the Expression Profile of Autophagy-Related Genes in Colon Adenocarcinoma

Contact Info

Product

Resources

About