Yorkie drives Ras-induced tumor progression by microRNA-mediated inhibition of cellular senescence

2021 ◽  
Vol 14 (685) ◽  
pp. eaaz3578
Author(s):  
Takao Ito ◽  
Tatsushi Igaki
Keyword(s):  
Tumor Progression ◽  
Cell Polarity ◽  
Cellular Senescence ◽  
Mechanistic Explanation ◽  
Early Event ◽  
Ras Signaling ◽  
Ras Activation ◽  
Dependent Inhibition ◽  
Ets Family ◽  
Necessary And Sufficient

The activation of Ras signaling is a major early event of oncogenesis in many contexts, yet paradoxically, Ras signaling induces cellular senescence, which prevents tumorigenesis. Thus, Ras-activated cells must overcome senescence to develop into cancer. Through a genetic screen in Drosophila melanogaster, we found that the ETS family transcriptional activator Pointed (Pnt) was necessary and sufficient to trigger cellular senescence upon Ras activation and blocked Ras-induced tumor growth in eye-antennal discs. Through analyses of mosaic discs using various genetic tools, we identified a mechanism of tumor progression in which loss of cell polarity, a common driver of epithelial oncogenesis, abrogated Ras-induced cellular senescence through microRNA-mediated inhibition of Pnt. Mechanistically, polarity defects in Ras-activated cells caused activation of the Hippo effector Yorkie (Yki), which induced the expression of the microRNA bantam. bantam-mediated repression of the E3 ligase–associated protein Tribbles (Trbl) relieved Ras- and Akt-dependent inhibition of the transcription factor FoxO. The restoration of FoxO activity in Ras-activated cells induced the expression of the microRNAs miR-9c and miR-79, which led to reduced pnt expression, thereby abrogating cellular senescence and promoting tumor progression. Our findings provide a mechanistic explanation for how Ras-activated tumors progress toward malignancy by overcoming cellular senescence.

scholarly journals Hematopoietic Cell Fate and the Initiation of Leukemic Properties in Primitive Primary Human Cells Are Influenced by Ras Activity and Farnesyltransferase Inhibition

2004 ◽  
Vol 24 (16) ◽  
pp. 6993-7002 ◽  
Author(s):  
Craig Dorrell ◽  
Katsuto Takenaka ◽  
Mark D. Minden ◽  
Robert G. Hawley ◽  
John E. Dick
Keyword(s):  
Cell Fate ◽  
Myeloid Cell ◽  
Early Event ◽  
Ras Signaling ◽  
Human Leukemia ◽  
Ras Pathway ◽  
Hematopoietic Malignancies ◽  
Ras Activation ◽  
Elevated Frequency ◽  
High Level

ABSTRACT The Ras pathway transduces divergent signals determining normal cell fate and is frequently activated in hematopoietic malignancies, but the manner in which activation contributes to human leukemia is poorly understood. We report that a high level of activated H-Ras signaling in transduced primary human hematopoietic progenitors reduced their proliferation and enhanced monocyte/macrophage differentiation. However, the exposure of these cells to a farnesyltransferase inhibitor and establishment of a moderate level of Ras activity showed increased proliferation, an elevated frequency of primitive blast-like cells, and progenitors with enhanced self-renewal capacity. These results suggest that the amplitude of Ras pathway signaling is a determinant of myeloid cell fate and that moderate Ras activation in primitive hematopoietic cells can be an early event in leukemogenesis.

scholarly journals A systems mechanism for KRAS mutant allele–specific responses to targeted therapy

2019 ◽  
Vol 12 (600) ◽  
pp. eaaw8288 ◽  
Author(s):  
Thomas McFall ◽  
Jolene K. Diedrich ◽  
Meron Mengistu ◽  
Stacy L. Littlechild ◽  
Kendra V. Paskvan ◽  
...  
Keyword(s):  
Genomic Medicine ◽  
Interaction Strength ◽  
Growth Factor Receptor ◽  
Mechanistic Explanation ◽  
Ras Signaling ◽  
Wild Type ◽  
Independent Manner ◽  
Egfr Inhibition ◽  
Ras Activation ◽  
Allele Specific

Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient’s tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, that which encodes the G13D mutant protein (KRASG13D) behaves differently; for unknown reasons, KRASG13D CRC patients benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it contradicts the well-established mechanisms of EGFR signaling with regard to RAS mutations. Here, we identified a systems-level, mechanistic explanation for why KRASG13D cancers respond to EGFR inhibition. A computational model of RAS signaling revealed that the biophysical differences between the three most common KRAS mutants were sufficient to generate different sensitivities to EGFR inhibition. Integrated computation with experimentation then revealed a nonintuitive, mutant-specific dependency of wild-type RAS activation by EGFR that is determined by the interaction strength between KRAS and the tumor suppressor neurofibromin (NF1). KRAS mutants that strongly interacted with and competitively inhibited NF1 drove wild-type RAS activation in an EGFR-independent manner, whereas KRASG13D weakly interacted with and could not competitively inhibit NF1 and, thus, KRASG13D cells remained dependent on EGFR for wild-type RAS activity. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies.

scholarly journals The Formation of an Insulin-responsive Vesicular Cargo Compartment Is an Early Event in 3T3-L1 Adipocyte Differentiation

1999 ◽  
Vol 10 (5) ◽  
pp. 1581-1594 ◽  
Author(s):  
Amr K. El-Jack ◽  
Konstantin V. Kandror ◽  
Paul F. Pilch
Keyword(s):  
Glucose Transport ◽  
Glucose Transporter ◽  
Adipocyte Differentiation ◽  
Receptor Trafficking ◽  
Early Event ◽  
Glucose Transporter 1 ◽  
Glut4 Expression ◽  
Velocity Gradients ◽  
Dependent Inhibition ◽  
Intracellular Glucose

Differentiating 3T3-L1 cells exhibit a dramatic increase in the rate of insulin-stimulated glucose transport during their conversion from proliferating fibroblasts to nonproliferating adipocytes. On day 3 of 3T3-L1 cell differentiation, basal glucose transport and cell surface transferrin binding are markedly diminished. This occurs concomitant with the formation of a distinct insulin-responsive vesicular pool of intracellular glucose transporter 1 (GLUT1) and transferrin receptors as assessed by sucrose velocity gradients. The intracellular distribution of the insulin-responsive aminopeptidase is first readily detectable on day 3, and its gradient profile and response to insulin at this time are identical to that of GLUT1. With further time of differentiation, GLUT4 is expressed and targeted to the same insulin-responsive vesicles as the other three proteins. Our data are consistent with the notion that a distinct insulin-sensitive vesicular cargo compartment forms early during fat call differentiation and its formation precedes GLUT4 expression. The development of this compartment may result from the differentiation-dependent inhibition of constitutive GLUT1 and transferrin receptor trafficking such that there is a large increase in, or the new formation of, a population of postendosomal, insulin-responsive vesicles.

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.

scholarly journals Isoform-specific Ras signaling is growth factor dependent

2019 ◽  
Vol 30 (9) ◽  
pp. 1108-1117 ◽  
Author(s):  
Fiona E. Hood ◽  
Bertram Klinger ◽  
Anna U. Newlaczyl ◽  
Anja Sieber ◽  
Mathurin Dorel ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Ectopic Expression ◽  
In Vivo Studies ◽  
Ras Signaling ◽  
Oncogenic Ras ◽  
Ras Activation ◽  
Pathway Activation ◽  
Ras Isoforms

HRAS, NRAS, and KRAS isoforms are almost identical proteins that are ubiquitously expressed and activate a common set of effectors. In vivo studies have revealed that they are not biologically redundant; however, the isoform specificity of Ras signaling remains poorly understood. Using a novel panel of isogenic SW48 cell lines endogenously expressing wild-type or G12V-mutated activated Ras isoforms, we have performed a detailed characterization of endogenous isoform-specific mutant Ras signaling. We find that despite displaying significant Ras activation, the downstream outputs of oncogenic Ras mutants are minimal in the absence of growth factor inputs. The lack of mutant KRAS-induced effector activation observed in SW48 cells appears to be representative of a broad panel of colon cancer cell lines harboring mutant KRAS. For MAP kinase pathway activation in KRAS-mutant cells, the requirement for coincident growth factor stimulation occurs at an early point in the Raf activation cycle. Finally, we find that Ras isoform-specific signaling was highly context dependent and did not conform to the dogma derived from ectopic expression studies.

scholarly journals Effect of Angiotensin II and Small GTPase Ras Signaling Pathway Inhibition on Early Renal Changes in a Murine Model of Obstructive Nephropathy

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Ana B. Rodríguez-Peña ◽  
Isabel Fuentes-Calvo ◽  
Neil G. Docherty ◽  
Miguel Arévalo ◽  
María T. Grande ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Akt Signaling ◽  
Small Gtpase ◽  
Tubulointerstitial Fibrosis ◽  
Ras Signaling ◽  
Signaling System ◽  
Ras Activation ◽  
Renal Tubulointerstitial Fibrosis

Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, andα-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.

scholarly journals Phyllopod Acts as an Adaptor Protein To Link the Sina Ubiquitin Ligase to the Substrate Protein Tramtrack

2002 ◽  
Vol 22 (19) ◽  
pp. 6854-6865 ◽  
Author(s):  
Songhui Li ◽  
Chunyan Xu ◽  
Richard W. Carthew
Keyword(s):  
Ubiquitin Ligase ◽  
Neuronal Development ◽  
Adaptor Protein ◽  
Ras Signaling ◽  
Binding Domains ◽  
Substrate Protein ◽  
Ras Activation ◽  
Ubiquitin Ligase Complex ◽  
Acid Domain ◽  
F Box Protein

ABSTRACT The RING domain protein Sina, together with Phyllopod and the F-box protein Ebi, forms a Ras-regulated E3 ubiquitin ligase complex that activates photoreceptor cell differentiation in the eye of Drosophila melanogaster. The expression of Phyllopod is induced upon Ras activation, allowing the complex to degrade the transcription repressor Tramtrack and removing its block of neuronal development in photoreceptor precursors. We show that Phyllopod functions as an adaptor in the complex, physically linking Sina with Tramtrack via separate binding domains. One 19-amino-acid domain in Phyllopod interacts with a region of Sina's SBD domain. Another domain in Phyllopod interacts with a C-terminal helix in the POZ domain of Tramtrack. This interaction is specific to the Tramtrack POZ domain and not to other POZ domain proteins present in photoreceptor precursors. Degradation of Tramtrack is dependent upon association of Sina with its cognate binding site in Phyllopod. These results illustrate how Ras signaling can modulate an E3 ligase activity not by the phosphorylation of substrate proteins but by regulating the expression of specific E3 adaptors.

Sign in / Sign up

Export Citation Format

Share Document