Gene Expression Profile Associated with Oncogenic Ras-induced Senescence, Cell Death, and Transforming Properties in Human Cells

Moumtzi, Sophy; Roberts, Michael L.; Joyce, Tobias; Evangelidou, Maria; Probert, Lesley; Frillingos, Stathis; Fotsis, Theodore; Pintzas, Alexander

doi:10.3109/07357900903095623

Cited by 7 publications

(3 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to hyper-methylation that suppresses the translation of genes, hypomethylation enables genes to be "released" and start replication and translation. These abnormally expressed proteins trigger an intracellular response, much like hyperexpression of Ras in mammal MSCs triggers activation of tumor suppression pathways, and thus induces irreversible growth arrest (Moumtzi, 2010). In the presence of the hyperproliferative signals during the process of senescence, cells encounter a strong DNA replication stress and finally develop numerous double-stranded DNA breaks (DSBs) in fragile areas of DNA (Hladik, 2019).…”

Section: Oncogene-induced Senescencementioning

confidence: 99%

Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges

Xueke

Hong

Zhang

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Over the past decades, mesenchymal stem cell (MSC)-based therapy has been intensively investigated and shown promising results in the treatment of various diseases due to their easy isolation, multiple lineage differentiation potential and immunomodulatory effects. To date, hundreds of phase I and II clinical trials using MSCs have been completed and many are ongoing. Accumulating evidence has shown that transplanted allogeneic MSCs lose their beneficial effects due to immunorejection. Nevertheless, the function of autologous MSCs is adversely affected by age, a process termed senescence, thus limiting their therapeutic potential. Despite great advances in knowledge, the potential mechanisms underlying MSC senescence are not entirely clear. Understanding the molecular mechanisms that contribute to MSC senescence is crucial when exploring novel strategies to rejuvenate senescent MSCs. In this review, we aim to provide an overview of the biological features of senescent MSCs and the recent progress made regarding the underlying mechanisms including epigenetic changes, autophagy, mitochondrial dysfunction and telomere shortening. We also summarize the current approaches to rejuvenate senescent MSCs including gene modification and pretreatment strategies. Collectively, rejuvenation of senescent MSCs is a promising strategy to enhance the efficacy of autologous MSC-based therapy, especially in elderly patients.

show abstract

Section: Oncogene-induced Senescencementioning

confidence: 99%

Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges

Xueke

Hong

Zhang

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Numerous investigations were based e.g. on transcriptome (Huang et al, 2003; Moumtzi et al, 2010; Tchernitsa et al, 2004; Zuber et al, 2000), proteome (Li et al, 2016; Rignall et al, 2009), membrane proteome (Martinko et al, 2018), the secretome (Demory Beckler et al, 2013), glycoproteome (Sudhir et al, 2012) and metabolome analysis (Hutton et al, 2016). In addition, RAS pathway-associated gene signatures were described in cancer cell lines and tumour tissue (Bild et al, 2006; Li et al, 2016; Loboda et al, 2010; Rignall et al, 2009; Stephens et al, 2017; Sweet-Cordero et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Up-regulated transcriptional regulators in mutant RAS gene signatures: a time-resolved multi-omics study in generic epithelial cell models

Kasack,

Metzger,

Koch

et al. 2024

Preprint

View full text Add to dashboard Cite

The expression of mutated RAS genes drives extensive transcriptome alterations. Perturbation experiments have shown that the transcriptional responses to downstream effector pathways are partially unique and non-overlapping, suggesting a modular organization of the RAS-driven expression program. However, the relationship between individual deregulated transcription factors and the entire cancer cell-specific genetic program is poorly understood. To identify potential regulators of the RAS/MAPK-dependent fraction of the genetic program, we monitored transcriptome and proteome changes following conditional, time-resolved expression of mutant HRASG12Vin human epithelial cells during neoplastic conversion. High mobility group AT hook2 (HMGA2), an architectural chromatin modulating protein and oncofetal tumour marker, was recovered as the earliest upregulated transcription factor. Knock-down of HMGA2 reverted anchorage-independent growth and epithelial-mesenchymal transition not only in HRAS-transformed cells but also in an independent, KRASG12V-driven rat epithelial model. Moreover, HMGA2 silencing reverted the deregulated expression of 60% of RAS-responsive target genes. These features qualify HMGA2 as a master regulator of mutant RAS-driven expression patterns. The delayed deregulation of FOSL1, ZEB1 and other transcription factors with known oncogenic activity suggests that HMGA2 acts in concert with a network of regulatory factors to trigger full neoplastic conversion. Although transcription factors are considered difficult to drug, the central role of HMGA2 in the transcription factor network as well as its relevance for cancer prognosis has motivated attempts to block its function using small molecular weight compounds. The further development of direct HMGA2 antagonists may prove useful in cancer cells that have developed resistance to signalling chain inhibition.

show abstract

“…This form of senescence, called "oncogene-induced senescence" (oncogene induced CS), is displayed by a variety of cell types (17). Oncogene induced CS is rapidly activated when oncogenic stress is present, resulting in the death of neoplastic cells in vitro (18). However, the role of oncogene induced CS in vivo is not clear, although data gathered by some authors have shown that oncogene induced CS could also serve as an in vivo antitumoral mechanism.…”

Section: Introductionmentioning

confidence: 99%

Senescence; an endogenous anticancer mechanism

Vargas

Feltes²,

F³

et al. 2012

Front Biosci

View full text Add to dashboard Cite

Pre-malignant tumor cells enter a state of irreversible cell cycle arrest termed senescence (cellular senescence; CS). CS is a part of the aging program and involves multiple signaling cascades and transduction mechanisms. In general, senescence can be divided into replicative senescence and premature senescence. Replicative senescence (replicative CS) has been described for all metabolically active cells that undergo a spontaneous decline in growth rate. Notably, ectopic expression of telomerase holoenzyme (hTert) can prevent replicative CS. In cancer cells, premature senescence induced by oncogenes, named oncogene-induced senescence (oncogene induced CS; OIS), play an important role in preventing the development of cancer. Oncogene induced CS can be promoted by the loss of tumor suppressor genes, such as PTEN. Additionally, other interesting mechanisms, like selective microRNA expression, epigenetic modifications, or even stress conditions, are also able to activate the senescence program. Here, we will critically review the literature on the role of senescence in preventing the development of cancer and discuss the potential of senescence modulation for generating new molecular tools that could be explored as anticancer treatments.

show abstract

Gene Expression Profile Associated with Oncogenic Ras-induced Senescence, Cell Death, and Transforming Properties in Human Cells

Cited by 7 publications

References 44 publications

Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges

Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges

Up-regulated transcriptional regulators in mutant RAS gene signatures: a time-resolved multi-omics study in generic epithelial cell models

Senescence; an endogenous anticancer mechanism

Contact Info

Product

Resources

About