Interaction between NBS1 and the mTOR/Rictor/SIN1 Complex through Specific Domains

Yan

Genes Chromosomes & Cancer

et al. 2019

Hypoxia‐induced epithelial‐mesenchymal transition (EMT) involves the interplay between chromatin modifiers histone deacetylase 3 (HDAC3) and WDR5. The histone mark histone 3 lysine 4 acetylation (H3K4Ac) is observed in the promoter regions of various EMT marker genes (eg, CDH1 and VIM). To further define the genome‐wide location of H3K4Ac, a chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP‐seq) analysis was performed using a head and neck squamous cell carcinoma (HNSCC) FaDu cell line under normoxia and hypoxia. H3K4Ac was found to be located mainly around the transcription start site. Coupled with analysis of gene expression by RNA sequencing and using a HDAC3 knockdown cell line, 10 new genes (BMI1, GLI1, SMO, FOXF1, SIRT2, etc) that were labeled by H3K4Ac and regulated by HDAC3 were identified. Overexpression or knockdown of GLI1/SMO increased or repressed the in vitro migration and invasion activity in OECM‐1/FaDu cells, respectively. In HNSCC patients, coexpression of GLI1 and SMO in primary tumors correlated with metastasis. Our results identify new EMT marker genes that may play a significant role in hypoxia‐induced EMT and metastasis and further provide diagnostic and prognostic implications.

Section: Methodsmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Identification of new hypoxia‐regulated epithelial‐mesenchymal transition marker genes labeled by H3K4 acetylation

Yan

Genes Chromosomes & Cancer

et al. 2019

Journal of Surgical Oncology

“…Mucinous tumors were more likely to have CNA gain of the ARRDC gene ( P = .018) which works as a regulator of cancer growth and progression by binding to integrin beta 4, a tumor‐related antigen . Mucinous tumors were also more likely to have CNA gain of the RICTOR gene which is involved in the regulation of cell growth and survival through the mTOR and RET signaling pathways . Mucinous tumors were more likely to have CNA loss of the RASA1 gene in the MSS cohort only ( P = .0304).…”

Section: Resultsmentioning

confidence: 99%

“…23 Mucinous tumors were also more likely to have CNA gain of the RICTOR gene which is involved in the regulation of cell growth and survival through the mTOR and RET signaling pathways. [24][25][26][27][28] Mucinous tumors were more likely to have CNA loss of the RASA1 gene in the MSS cohort only (P = .0304). This gene is responsible for producing a protein that regulates the RAS/ mitogen-activated protein kinase (MAPK) signaling pathway, the protein normally works as a negative regulator of the RAS/MAPK signaling pathway meaning that it can switch-off signaling in this pathway when it is not needed.…”

mentioning

confidence: 99%

Mucinous adenocarcinoma of the colon and rectum: A genomic analysis

Reynolds

OʼConnell

Fichtner

et al. 2019

Background and Objectives Mucinous adenocarcinoma is a distinct subtype of colorectal cancer (CRC) with a worse prognosis when compared with non‐mucinous adenocarcinoma. The aim of this study was to compare somatic mutations and copy number alteration (CNA) between mucinous and non‐mucinous CRC. Methods Data from The Cancer Genome Atlas‐colon adenocarcinoma and rectum adenocarcinoma projects were utilized. Mucinous and non‐mucinous CRC were compared with regard to microsatellite status, overall mutation rate, the most frequently mutated genes, mutations in genes coding for mismatch repair (MMR) proteins and genes coding for mucin glycoproteins. CNA analysis and pathway analysis was undertaken. Results Mucinous CRC was more likely to be microsatellite instability‐high (MSI‐H) and hypermutated. When corrected for microsatellite status the single‐nucleotide variation and insertion‐deletion rate was similar between the two cohorts. Mucinous adenocarcinoma was more likely to have mutations in genes coding for MMR proteins and mucin glycoproteins. Pathway analysis revealed further differences between the two histological subtypes in the cell cycle, RTK‐RAS, transforming growth factor‐β, and TP53 pathways. Conclusions Mucinous CRC has some distinct genomic aberrations when compared with non‐mucinous adenocarcinoma, many of which are driven by the increased frequency of MSI‐H tumors. These genomic aberrations may play an important part in the difference seen in response to treatment and prognosis in mucinous adenocarcinoma.

“… 6 Yet each of the mTOR complexes possesses a unique subset of components. RAPTOR 7 , 8 and PRAS40 9 - 13 can only be found in mTORC1, whereas RICTOR, 14 SIN1, 15 - 17 PROTOR, 18 XPLN, 19 NBS1, 20 IKKα and IKKβ 21 are specific to mTORC2 ( Fig. 1 ).…”

Section: Introduction To the Mtor Complexesmentioning

confidence: 97%

Signaling crosstalk between the mTOR complexes

Xie

Proud

2014

Translation

mTOR is a protein kinase which integrates a variety of environmental and intracellular stimuli to positively regulate many anabolic processes of the cell, including protein synthesis. It exists within two highly conserved multi-protein complexes known as mTORC1 and 2 mTORC2. Each of these complexes phosphorylates different downstream targets, and play roles in different cellular functions. They also show distinctive sensitivity to the mTOR inhibitor rapamycin. Nevertheless, despite their biochemical and functional differences, recent studies have suggested that the regulation of these complexes is tightly linked to each other. For instance, both mTORC1 and 2 share some common upstream signaling molecules, such as PI3K and tuberous sclerosis complex TSC, which control their activation. Stimulation of the mTOR complexes may also trigger both positive and negative feedback mechanisms, which then in turn either further enhance or suppress their activation. Here, we summarize some recently discovered features relating to the crosstalk between mTORC1 and 2. We then discuss how aberrant mTOR complex crosstalk mechanisms may have an impact on the development of human diseases and drug resistance.