Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

Wang, Yihua; Ngo, Vu N.; Marani, Michela; Yang, Yandan; Wright, George W.; Staudt, Louis M.; Downward, Julian

doi:10.1038/onc.2010.218

Cited by 103 publications

(74 citation statements)

References 51 publications

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“…Direct inhibition of RAS activity has not met with great success [62], but targeting of downstream signalling molecules (such as RAF and MEK) holds promise [63]. In addition, synthetic lethality screens have identified potential targets selective to RAS mutant cells [64]. We did not find statistically significant differences in the CTL recognition of H Mu and H WT cells.…”

Section: Discussionmentioning

confidence: 44%

Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes

El-Jawhari

El-Sherbiny

Scott

et al. 2014

Molecular Immunology

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Section: Discussionmentioning

confidence: 44%

Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes

El-Jawhari

El-Sherbiny

Scott

et al. 2014

Molecular Immunology

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“…Although L1 expression in CRC cells did not confer an EMT signature, overexpression of Ras in CRC cells was shown to result (by gene expression profiling) in the induction of an EMT-like signature (33,34). Because L1-mediated metastasis in CRC cells requires NF-kB signaling in cells expressing different E-cadherin levels (this study and ref.…”

Section: Discussionmentioning

confidence: 99%

L1-Mediated Colon Cancer Cell Metastasis Does Not Require Changes in EMT and Cancer Stem Cell Markers

Gavert

Vivanti

Hazin

et al. 2011

Molecular Cancer Research

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Aberrant activation of Wnt/b-catenin signaling is common in most sporadic and inherited colorectal cancer (CRC) cells leading to elevated b-catenin/TCF transactivation. We previously identified the neural cell adhesion molecule L1 as a target gene of b-catenin/TCF in CRC cells. Forced expression of L1 confers increased cell motility, invasion, and tumorigenesis, and the induction of human CRC cell metastasis to the liver. In human CRC tissue, L1 is exclusively localized at the invasive front of such tumors in a subpopulation of cells displaying nuclear b-catenin. We determined whether L1 expression confers metastatic capacities by inducing an epithelial to mesenchymal transition (EMT) and whether L1 cosegregates with cancer stem cell (CSC) markers. We found that changes in L1 levels do not affect the organization or expression of E-cadherin in cell lines, or in invading CRC tissue cells, and no changes in other epithelial or mesenchymal markers were detected after L1 transfection. The introduction of major EMT regulators (Slug and Twist) into CRC cell lines reduced the levels of E-cadherin and induced fibronectin and vimentin, but unlike L1, Slug and Twist expression was insufficient for conferring metastasis. In CRC cells L1 did not specifically cosegregate with CSC markers including CD133, CD44, and EpCAM. L1-mediated metastasis required NF-kB signaling in cells harboring either high or low levels of endogenous E-cadherin. The results suggest that L1-mediated metastasis of CRC cells does not require changes in EMT and CSC markers and operates by activating NF-kb signaling. Mol Cancer Res; 9(1); 14-24. Ó2010 AACR.

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“…To investigate how ASPP2 inhibits RAS autophagy and to demonstrate that this property of ASPP2 is not specific to MEFs, we used a pair of isogenic human colon cancer cell lines: HCT116 and its isogenic counterpart HKe3, which was created by genetic disruption of the activated KRAS allele in HCT116 (23). HKe3 cells were transduced with a regulatable RAS construct made up of mutant HRAS fused to the ER ligand-binding domain that is conditionally responsive to 4-OHT: HKe3 ER: HRAS V12 cells (24,25). Further, knowing that the N-terminal ASPP2 region is required and sufficient to inhibit RAS-induced autophagy, we hypothesized that the newly identified property of ASPP2 should also exist in ASPP1 but not in inhibitor of apoptosis-stimulating protein of p53 (iASPP).…”

Section: Aspp2 Inhibits Autophagy By Preventing Atg16/atg5/atg12 Complexmentioning

confidence: 99%

Autophagic activity dictates the cellular response to oncogenic RAS

Wang

Lapi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

109

124

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RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2 (Δ3/Δ3) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.A ctive mutations of RAS, one of the first oncogenes identified, occur in about 20% of human tumors (1). Oncogenic RAS can transform cells and promote tumorigenesis, although it can also induce senescence and suppress tumor growth (2). Senescent cells are arrested and incapable of responding to mitogens, although they are viable and metabolically active. Senescence is characterized by dramatic cellular remodelling, which is energetically demanding. Autophagy, a genetically regulated process responsible for the turnover of cellular proteins and damaged or superfluous organelles, is a stress response involved in energy homeostasis (3). It was shown that autophagy is a critical mediator of oncogenic RAS-induced senescence, suggesting a negative role of autophagy in tumorigenesis (4). In contrast, a number of recent studies showed that active RAS requires autophagy to maintain its oncogenic function in tumorigenesis, arguing for a positive role of autophagy in tumorigenesis (5-8). The underlying reason for the conflicting observations remains unclear.RAS activation inhibits autophagy by activating the PI3K/ AKT/mammalian target of rapamycin (mTOR) pathway (9), and rapamycin, an mTOR inhibitor, is a potent inducer of autophagy. RAS also inhibits autophagy by reducing Beclin-1 expression in intestinal epithelial cells, an important mediator of autophagy (10). However, RAS was reported to induce autophagy by increasing the expression of key components of the autophagy machinery, such as ATG5 (11) and Beclin-1 (12). These reports suggest that RAS signaling performs a finely regulated balancing act to control autophagy. Identification of switching molecules that determine the cellular responses to RAS is thus needed urgently.The tumor suppressor p53 is one of the most well-established pathways by which RAS mediates cellular senescence. A recent study also showed that p53 is able to regulate autophagic activity by inducing the expression of LC3 (13). However, it remains unknown whether the abilit...

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Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

Cited by 103 publications

References 51 publications

Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes

Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes

L1-Mediated Colon Cancer Cell Metastasis Does Not Require Changes in EMT and Cancer Stem Cell Markers

Autophagic activity dictates the cellular response to oncogenic RAS

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