scholarly journals Cooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yong-Li Dong ◽  
Gangadhara P. Vadla ◽  
Jin-Yu (Jim) Lu ◽  
Vakil Ahmad ◽  
Thomas J. Klein ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Cellular Response ◽  
Cell Communication ◽  
Genotoxic Stress ◽  
Tumor Resistance ◽  
Wild Type ◽  
Therapy Outcomes ◽  
Oncogenic Ras ◽  
Tumor Tissues ◽  
Cell Cell

AbstractOncogenic RAS mutations are associated with tumor resistance to radiation therapy. Cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. However, the nature of these interactions and their role in Ras tumor radioresistance remain unclear. Here we use Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discover that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. Specifically, p53 is heterogeneously activated in Ras tumor tissues in response to irradiation. This mosaicism allows high p53-expressing Ras clones to stimulate JAK/STAT cytokines, which activate JAK/STAT in the nearby low p53-expressing surviving Ras clones, leading to robust tumor re-establishment. Blocking any part of this cell-cell communication loop re-sensitizes Ras tumor cells to irradiation. These findings suggest that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients.

scholarly journals Cooperation between oncogenic Ras and p53 stimulates JAK/STAT non-cell autonomously to promote Ras tumor radioresistance

2020 ◽  
Author(s):  
Yong-Li Dong ◽  
Ganghadara P Valdka ◽  
Jin-Yu (Jim) Lu ◽  
Vakil Ahmad ◽  
Thomas J. Klein ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cellular Response ◽  
Cell Communication ◽  
Genotoxic Stress ◽  
Tumor Resistance ◽  
Therapy Outcomes ◽  
Oncogenic Ras ◽  
Tumor Tissues ◽  
Underlying Mechanisms ◽  
Cell Cell

AbstractOncogenic RAS mutations are associated with tumor resistance to radiation therapy. The underlying mechanisms remain unclear. Emergent cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. The nature of these interactions and their role in Ras tumor radioresistance remain unclear. We used Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discovered that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. JAK/STAT accelerates the growth of the less-damaged Ras tumor cells, leading to rapid tumor recurrence. Specifically, p53 is heterogeneously activated in Ras tumor tissues in response to irradiation. This mosaicism allows high p53-expressing Ras clones to stimulate JAK/STAT cytokines, which activate JAK/STAT in the nearby low p53-expressing surviving Ras clones, leading to robust tumor re-establishment. Blocking any part of this cell-cell communication loop re-sensitizes Ras tumor cells to irradiation. This finding suggests that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients.

scholarly journals A Cyclic AMP Receptor Protein-Regulated Cell-Cell Communication System Mediates Expression of a FecA Homologue in Stenotrophomonas maltophilia

2007 ◽  
Vol 73 (15) ◽  
pp. 5034-5040 ◽  
Author(s):  
Tzu-Pi Huang ◽  
Amy C. Lee Wong
Keyword(s):  
Cyclic Amp ◽  
Communication System ◽  
Stenotrophomonas Maltophilia ◽  
Environmental Changes ◽  
Cell Communication ◽  
Transcript Level ◽  
Ferric Citrate ◽  
Receptor Protein ◽  
Wild Type ◽  
Cell Cell

ABSTRACT Stenotrophomonas maltophilia WR-C possesses an rpf/diffusible signal factor (DSF) cell-cell communication system. It produces cis-Δ2-11-methyl-dodecenoic acid, a DSF, and seven structural derivatives, which require rpfF and rpfB for synthesis. Acquisition of iron from the environment is important for bacterial growth as well as the expression of virulence genes. We identified a gene homologous to fecA, which encodes a ferric citrate receptor that transports exogenous siderophore ferric citrate from the environment into the bacterial periplasm. Western blot analysis with anti-FecA-His6 antibody showed that the FecA homologue was induced in the iron-depleted medium supplemented with a low concentration of ferric citrate. Deletion of rpfF or rpfB resulted in reduced FecA expression compared to the wild type. Synthetic DSF restored FecA expression by the ΔrpfF mutant to the wild-type level. Reverse transcription-PCR showed that the fecA transcript was decreased in the ΔrpfF mutant compared to the wild type. These data suggest that DSF affected the level of fecA mRNA. Transposon inactivation of crp, which encodes cyclic AMP (cAMP) receptor protein (CRP) resulted in reduced FecA expression and rpfF transcript level. Putative CRP binding sites were located upstream of the rpfF promoter, indicating that the effect of CRP on FecA is through the rpf/DSF pathway and by directly controlling rpfF. We propose that CRP may serve as a checkpoint for iron uptake, protease activity, and hemolysis in response to environmental changes such as changes in concentrations of glucose, cAMP, iron, or DSF.

scholarly journals A Critical-like Collective State Leads to Long-range Cell Communication in Dictyostelium discoideum Aggregation

2016 ◽  
Author(s):  
Giovanna De Palo ◽  
Darvin Yi ◽  
Robert G. Endres
Keyword(s):  
Single Cell ◽  
Dictyostelium Discoideum ◽  
Long Range ◽  
Early Development ◽  
Cell Communication ◽  
Multiscale Model ◽  
Wild Type ◽  
Social Amoeba ◽  
Range Cell ◽  
Cell Cell

AbstractThe transition from single-cell to multicellular behavior is important in early development but rarely studied. The starvation-induced aggregation of the social amoeba Dictyostelium discoideum into a multicellular slug is known to result from single-cell chemotaxis towards emitted pulses of cyclic adenosine monophosphate (cAMP). However, how exactly do transient short-range chemical gradients lead to coherent collective movement at a macroscopic scale? Here, we developed a multiscale model verified by quantitative microscopy to describe wide-ranging behaviors from chemotaxis and excitability of individual cells to aggregation of thousands of cells. To better understand the mechanism of long-range cell-cell communication and hence aggregation, we analyzed cell-cell correlations, showing evidence of self-organization at the onset of aggregation (as opposed to following a leader cell). Surprisingly, cell collectives, despite their finite size, show features of criticality known from phase transitions in physical systems. By comparing wild-type and mutant cells with impaired aggregation, we found the longest cellcell communication distance in wild-type cells, suggesting that criticality provides an adaptive advantage and optimally sized aggregates for the dispersal of spores.Author SummaryCells are often coupled to each other in cell collectives, such as aggregates during early development, tissues in the developed organism, and tumors in disease. How do cells communicate over macroscopic distances much larger than the typical cell-cell distance to decide how they should behave? Here, we developed a multiscale model of social amoeba, spanning behavior from individuals to thousands of cells. We show that local cell-cell coupling via secreted chemicals may be tuned to a critical value, resulting in emergent long-range communication and heightened sensitivity. Hence, these aggregates are remarkably similar to bacterial biofilms and neuronal networks, all communicating in a pulse-like fashion. Similar organizing principles may also aid our understanding of the remarkable robustness in cancer development.

scholarly journals Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b

2000 ◽  
Vol 20 (8) ◽  
pp. 2915-2925 ◽  
Author(s):  
Marcos Malumbres ◽  
Ignacio Pérez De Castro ◽  
María I. Hernández ◽  
María Jiménez ◽  
Teresa Corral ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cellular Response ◽  
Cellular Transformation ◽  
Dominant Negative ◽  
Erk Pathway ◽  
Wild Type ◽  
Embryonic Fibroblasts ◽  
Oncogenic Ras ◽  
Cell Cycle Inhibitor

ABSTRACT The cell cycle inhibitor p15 INK4b is frequently inactivated by homozygous deletion together with p16 INK4a and p19 ARF in some types of tumors. Although the tumor suppressor capability of p15 INK4b is still questioned, it has been found to be specifically inactivated by hypermethylation in hematopoietic malignancies in the absence of p16 INK4a alterations. Here we show that, in vitro, p15 INK4b is a strong inhibitor of cellular transformation by Ras. Surprisingly, p15 INK4b is induced in cultured cells by oncogenic Ras to an extent similar to that of p16 INK4a , and their expression is associated with premature G1 arrest and senescence. Ras-dependent induction of these two INK4 genes is mediated mainly by the Raf-Mek-Erk pathway. Studies with activated and dominant negative forms of Ras effectors indicate that the Raf-Mek-Erk pathway is essential for induction of both the p15 INK4b and p16 INK4a promoters, although other Ras effector pathways can collaborate, giving rise to a stronger response. Our results indicate that p15 INK4b , by itself, is able to stop cell transformation by Ras and other oncogenes such as Rgr (a new oncogene member of the Ral-GDS family, whose action is mediated through Ras). In fact, embryonic fibroblasts isolated from p15 INK4b knockout mice are susceptible to transformation by the Ras or Rgr oncogene whereas wild-type embryonic fibroblasts are not. Similarly, p15 INK4b -deficient mouse embryo fibroblasts are more sensitive than wild-type cells to transformation by a combination of the Rgr and E1A oncogenes. The cell cycle inhibitor p15 INK4b is therefore involved, at least in some cell types, in the tumor suppressor activity triggered after inappropriate oncogenic Ras activation in the cell.

Investigation of the role of cell-cell interactions in division plane determination during maize leaf development through mosaic analysis of the tangled mutation

Development ◽  
2002 ◽  
Vol 129 (13) ◽  
pp. 3219-3226
Author(s):  
Keely L. Walker ◽  
Laurie G. Smith
Keyword(s):  
Cell Communication ◽  
Wild Type ◽  
Division Plane ◽  
Maize Leaf ◽  
Mosaic Analysis ◽  
Leaf Dimensions ◽  
Cell Autonomy ◽  
Mutant Cells ◽  
Cell Cell

Most plant cells divide in planes that can be predicted from their shapes according to simple geometrical rules, but the division planes of some cells appear to be influenced by extracellular cues. In the maize leaf, some cells divide in orientations not predicted by their shapes, raising the possibility that cell-cell communication plays a role in division plane determination in this tissue. We investigated this possibility through mosaic analysis of the tangled (tan) mutation, which causes a high frequency of cells in all tissue layers to divide in abnormal orientations. Clonal sectors of tan mutant tissue marked by a closely linked albino mutation were examined to determine the phenotypes of cells near sector boundaries. We found that tan mutant cells always showed the mutant phenotype regardless of their proximity to wild-type cells, demonstrating that the wild-type Tan gene acts cell-autonomously in both lateral and transverse leaf dimensions to promote normally oriented divisions. However, if the normal division planes of wild-type cells depend on cell-cell communication involving the products of genes other than Tan, then aberrantly dividing tan mutant cells might send abnormal signals that alter the division planes of neighboring cells. The cell-autonomy of the tan mutation allowed us to investigate this possibility by examining wild-type cells near the boundaries of tan mutant sectors for evidence of aberrantly oriented divisions. We found that wild-type cells near tan mutant cells did not divide differently from other wild-type cells. These observations argue against the idea that the division planes of proliferatively dividing maize leaf epidermal cells are governed by short-range communication with their nearest neighbors.

scholarly journals Poly(ADP-ribose) glycohydrolase silencing protects against H2O2-induced cell death

2006 ◽  
Vol 396 (3) ◽  
pp. 419-429 ◽  
Author(s):  
Christian Blenn ◽  
Felix R. Althaus ◽  
Maria Malanga
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Oxidative Dna Damage ◽  
Genotoxic Stress ◽  
Biological Functions ◽  
Wild Type ◽  
Cellular Functions ◽  
Early Embryonic Lethality ◽  
Sublethal Doses ◽  
Induced Apoptosis

PAR [poly(ADP-ribose)] is a structural and regulatory component of multiprotein complexes in eukaryotic cells. PAR catabolism is accelerated under genotoxic stress conditions and this is largely attributable to the activity of a PARG (PAR glycohydrolase). To overcome the early embryonic lethality of parg-knockout mice and gain more insights into the biological functions of PARG, we used an RNA interference approach. We found that as little as 10% of PARG protein is sufficient to ensure basic cellular functions: PARG-silenced murine and human cells proliferated normally through several subculturing rounds and they were able to repair DNA damage induced by sublethal doses of H2O2. However, cell survival following treatment with higher concentrations of H2O2 (0.05–1 mM) was increased. In fact, PARG-silenced cells were more resistant than their wild-type counterparts to oxidant-induced apoptosis while exhibiting delayed PAR degradation and transient accumulation of ADP-ribose polymers longer than 15-mers at early stages of drug treatment. No difference was observed in response to the DNA alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine, suggesting a specific involvement of PARG in the cellular response to oxidative DNA damage.

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