scholarly journals Promotion of cancer cell stemness by Ras

2021 ◽  
Author(s):  
Rohan Chippalkatti ◽  
Daniel Abankwa
Keyword(s):  
Cell Fate ◽  
Cancer Cell ◽  
Mapk Pathway ◽  
Cancer Genes ◽  
Cell Fate Decisions ◽  
Oncogenic Ras ◽  
Ras Activation ◽  
Cancer Cell Population ◽  
Cellular Machinery ◽  
Cycle Dependent

Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.

scholarly journals ZNF768 links oncogenic RAS to cellular senescence

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Romain Villot ◽  
Audrey Poirier ◽  
Inan Bakan ◽  
Karine Boulay ◽  
Erlinda Fernández ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Cancer Genomics ◽  
Ras Proteins ◽  
Oncogenic Signaling ◽  
Replicative Stress ◽  
Oncogenic Ras ◽  
Ras Activation ◽  
Fate Decision ◽  
Immunohistochemical Analyses

AbstractRAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incompletely characterized. Here, we identify ZNF768 as a phosphoprotein destabilized upon RAS activation. We report that ZNF768 depletion impairs proliferation and induces senescence by modulating the expression of key cell cycle effectors and established p53 targets. ZNF768 levels decrease in response to replicative-, stress- and oncogene-induced senescence. Interestingly, ZNF768 overexpression contributes to bypass RAS-induced senescence by repressing the p53 pathway. Furthermore, we show that ZNF768 interacts with and represses p53 phosphorylation and activity. Cancer genomics and immunohistochemical analyses reveal that ZNF768 is often amplified and/or overexpressed in tumors, suggesting that cells could use ZNF768 to bypass senescence, sustain proliferation and promote malignant transformation. Thus, we identify ZNF768 as a protein linking oncogenic signaling to the control of cell fate decision and proliferation.

A Dual Proto-Oncogenic and Tumor Suppressive Role of LRF/POKEMON In Hemopoietic Malignancies through Control of Cell Fate Decision

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-14-SCI-14
Author(s):  
Pier Paolo Pandolfi
Keyword(s):  
Cell Fate ◽  
Cellular Differentiation ◽  
Conflicts Of Interest ◽  
Human Cancer ◽  
Cellular Transformation ◽  
Related Factor ◽  
Cancer Genes ◽  
Cell Fate Decisions

Abstract Abstract SCI-14 LRF (Leukemia/lymphoma-related factor, also known as POKEMON) is a member of the POZ and Kruppel (POK) family of transcription factors. LRF has been shown to play an essential role in embryonic development and to act as a master regulator of cellular differentiation in virtually any tissue where it is found expressed, including the hemopoietic compartment. As we will discuss, LRF inactivation in the mouse blocks cellular differentiation in both myeloid/erythroid and lymphoid compartments. On the other hand, LRF has been shown to possess a potent proto-oncogenic activity both in vitro and in vivo. In fact, LRF itself can transform primary cells in combination with known oncogenes and is also essential for cellular transformation of mouse embryonic fibroblasts. In addition, overexpression of LRF in immature B and T progenitor cells in vivo in the mouse lead to lethal precursor T-cell lymphoblastic lymphoma/leukemia. In agreement with this notion, LRF is aberrantly expressed in a variety of human cancers, including diffuse large B cell and follicular lymphomas, but also ovarian and breast cancers. Further, the LRF gene is found amplified in a subset of non-small cell lung cancers (NSCLCs), illustrating a direct role in human cancer. However, we speculated that due to the key role of LRF in cell fate decisions, LRF/POKEMON loss could also contribute to tumorigenesis by blocking cellular differentiation. We will discuss provocative in vivo data in support of the notion that LRF/POKEMON can indeed act as a bona fide tumor suppressor representing a compelling example of two-faced cancer genes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Graded Mitogen-Activated Protein Kinase Activity Precedes Switch-Like c-Fos Induction in Mammalian Cells

2005 ◽  
Vol 25 (11) ◽  
pp. 4676-4682 ◽  
Author(s):  
Jeffrey P. MacKeigan ◽  
Leon O. Murphy ◽  
Christopher A. Dimitri ◽  
John Blenis
Keyword(s):  
Protein Kinase ◽  
Cell Fate ◽  
Oocyte Maturation ◽  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cell Fate Decisions ◽  
Graded Response ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) pathway is an evolutionarily conserved signaling module that controls important cell fate decisions in a variety of physiological contexts. During Xenopus oocyte maturation, the MAPK cascade converts an increasing progesterone stimulus into a switch-like, all-or-nothing response. While the importance of such switch-like behavior is widely discussed in the literature, it is not known whether the MAPK pathway in mammalian cells exhibits a switch-like or graded response. For this study, we used flow cytometry and immunofluorescence to generate single-cell measurements of MAPK signaling in Swiss 3T3 fibroblasts. In contrast to the case in Xenopus oocytes, we found that ERK activation in individual mammalian cells is not ultrasensitive and shows a graded response to changes in agonist concentration. Thus, the conserved MAPK signaling module exhibits different systems-level properties in different cellular contexts. Furthermore, the graded ERK response was converted into a more switch-like behavior at the level of immediate-early gene induction and cell cycle progression. Thus, while MAPK signaling is involved in all-or-nothing cell fate decisions for both Xenopus oocyte maturation and mammalian fibroblast proliferation, the underlying mechanisms responsible for the switch-like nature of the cellular responses are different in these two systems, with the mechanism appearing to lie downstream of the kinase cascade in mammalian fibroblasts.

Systems analysis of MAPK signal transduction

2008 ◽  
Vol 45 ◽  
pp. 95-108 ◽  
Author(s):  
Nils Blüthgen ◽  
Stefan Legewie
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Mapk Pathway ◽  
Experimental Studies ◽  
Mitogen Activated Protein Kinase ◽  
Cell Fate Decisions ◽  
Biological Responses ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Extracellular Stimuli

For more than a decade, the MAPK (mitogen-activated protein kinase) cascade has been studied using mathematical modelling and quantitative experimentation [1]. The MAPK cascade relays the presence of extracellular stimuli such as growth hormones to the nucleus and controls the expression of hundreds of genes. MAPKs control major cell fate decisions such as proliferation, differentiation and apoptosis, mainly by inducing alterations in gene expression. In this chapter, we discuss how systems biology analysis provides insights into the functioning of this cascade. We show how this pathway assists the cell in responding properly to extracellular cues by filtering out sub-threshold stimuli, while efficiently transmitting physiologically relevant inputs. Several different receptors signal through the MAPK pathway even though they elicit opposite biological responses, thus raising the question of how specificity is achieved in MAPK signalling. Experimental studies revealed that specific biological responses are encoded by quantitative aspects of the MAPK signal such as amplitude or duration. We discuss mechanisms that enable the pathway to generate quantitatively different signals, and also explain how different signals are interpreted by the downstream gene expression machinery.

scholarly journals Activation of the MAPK Module from Different Spatial Locations Generates Distinct System Outputs

2008 ◽  
Vol 19 (11) ◽  
pp. 4776-4784 ◽  
Author(s):  
Kerry Inder ◽  
Angus Harding ◽  
Sarah J. Plowman ◽  
Mark R. Philips ◽  
Robert G. Parton ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Fate ◽  
Mapk Pathway ◽  
Cell Fate Decisions ◽  
Raf Kinase ◽  
System Output ◽  
Multiple Cell ◽  
Spatial Locations ◽  
Distinct Membrane ◽  
Striking Contrast

The Ras/Raf/MEK/ERK (MAPK) pathway directs multiple cell fate decisions within a single cell. How different system outputs are generated is unknown. Here we explore whether activating the MAPK module from different membrane environments can rewire system output. We identify two classes of nanoscale environment within the plasma membrane. The first, which corresponds to nanoclusters occupied by GTP-loaded H-, N- or K-Ras, supports Raf activation and amplifies low Raf kinase input to generate a digital ERKpp output. The second class, which corresponds to nanoclusters occupied by GDP-loaded Ras, cannot activate Raf and therefore does not activate the MAPK module, illustrating how lateral segregation on plasma membrane influences signal output. The MAPK module is activated at the Golgi, but in striking contrast to the plasma membrane, ERKpp output is analog. Different modes of Raf activation precisely correlate with these different ERKpp system outputs. Intriguingly, the Golgi contains two distinct membrane environments that generate ERKpp, but only one is competent to drive PC12 cell differentiation. The MAPK module is not activated from the ER. Taken together these data clearly demonstrate that the different nanoscale environments available to Ras generate distinct circuit configurations for the MAPK module, bestowing cells with a simple mechanism to generate multiple system outputs from a single cascade.

scholarly journals Long Non-Coding RNAs in the Control of Gametogenesis: Lessons from Fission Yeast

2021 ◽  
Vol 7 (2) ◽  
pp. 34
Author(s):  
Vedrana Andric ◽  
Mathieu Rougemaille
Keyword(s):  
Fission Yeast ◽  
Cell Fate ◽  
Genetic Information ◽  
Developmental Process ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Fate Decisions ◽  
Genome Expression ◽  
Non Coding Rnas ◽  
Cycle Dependent

Long non-coding RNAs (lncRNAs) contribute to cell fate decisions by modulating genome expression and stability. In the fission yeast Schizosaccharomyces pombe, the transition from mitosis to meiosis results in a marked remodeling of gene expression profiles, which ultimately ensures gamete production and inheritance of genetic information to the offspring. This key developmental process involves a set of dedicated lncRNAs that shape cell cycle-dependent transcriptomes through a variety of mechanisms, including epigenetic modifications and the modulation of transcription, post-transcriptional and post-translational regulations, and that contribute to meiosis-specific chromosomal events. In this review, we summarize the biology of these lncRNAs, from their identification to mechanism of action, and discuss their regulatory role in the control of gametogenesis.

Cell cycle-dependent sequencing of cell fate decisions in Caenorhabditis elegans vulva precursor cells

Development ◽  
1999 ◽  
Vol 126 (9) ◽  
pp. 1947-1956 ◽  
Author(s):  
V. Ambros
Keyword(s):  
Cell Cycle ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Precursor Cells ◽  
S Phase ◽  
Cycle Phase ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Cycle Arrest ◽  
Cycle Dependent

In Caenorhabditis elegans, the fates of the six multipotent vulva precursor cells (VPCs) are specified by extracellular signals. One VPC expresses the primary (1 degrees) fate in response to a Ras-mediated inductive signal from the gonad. The two VPCs flanking the 1 degrees cell each express secondary (2 degrees) fates in response to lin-12-mediated lateral signaling. The remaining three VPCs each adopt the non-vulval tertiary (3 degrees) fate. Here I describe experiments examining how the selection of these vulval fates is affected by cell cycle arrest and cell cycle-restricted lin-12 activity. The results suggest that lin-12 participates in two developmental decisions separable by cell cycle phase: lin-12 must act prior to the end of VPC S phase to influence a 1 degrees versus 2 degrees cell fate choice, but must act after VPC S phase to influence a 3 degrees versus 2 degrees cell fate choice. Coupling developmental decisions to cell cycle transitions may provide a mechanism for prioritizing or ordering choices of cell fates for multipotential cells.

scholarly journals The hypoxia-response pathway modulates RAS/MAPK–mediated cell fate decisions in Caenorhabditis elegans

2019 ◽  
Vol 2 (3) ◽  
pp. e201800255 ◽  
Author(s):  
Sabrina Maxeiner ◽  
Judith Grolleman ◽  
Tobias Schmid ◽  
Jan Kammenga ◽  
Alex Hajnal
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Oxygen Concentration ◽  
Mapk Pathway ◽  
Atmospheric Oxygen ◽  
Mapk Signaling ◽  
Nuclear Hormone Receptor ◽  
Induced Differentiation ◽  
Hypoxia Response ◽  
Cell Fate Decisions

Animals need to adjust many cellular functions to oxygen availability to adapt to changing environmental conditions. We have used the nematode Caenorhabditis elegans as a model to investigate how variations in oxygen concentrations affect cell fate specification during development. Here, we show that several processes controlled by the conserved RTK/RAS/MAPK pathway are sensitive to changes in the atmospheric oxygen concentration. In the vulval precursor cells (VPCs), the hypoxia-inducible factor HIF-1 activates the expression of the nuclear hormone receptor NHR-57 to counteract RAS/MAPK–induced differentiation. Furthermore, cross-talk between the NOTCH and hypoxia-response pathways modulates the capability of the VPCs to respond to RAS/MAPK signaling. Lateral NOTCH signaling positively regulates the prolyl hydroxylase EGL-9, which promotes HIF-1 degradation in uncommitted VPCs and permits RAS/MAPK–induced differentiation. By inducing DELTA family NOTCH ligands, RAS/MAPK signaling creates a positive feedback loop that represses HIF-1 and NHR-57 expression in the proximal VPCs and keeps them capable of differentiating. This regulatory network formed by the NOTCH, hypoxia, and RAS/MAPK pathways may allow the animals to adapt developmental processes to variations in oxygen concentration.

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