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 Targeting oncogenic Ras signaling in hematologic malignancies

Blood ◽  
2012 ◽  
Vol 120 (17) ◽  
pp. 3397-3406 ◽  
Author(s):  
Ashley F. Ward ◽  
Benjamin S. Braun ◽  
Kevin M. Shannon
Keyword(s):  
Drug Discovery ◽  
Cell Fate ◽  
Hematologic Malignancies ◽  
Biochemical Properties ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Ras Mutations ◽  
Surface Receptors ◽  
Hematopoietic Malignancies ◽  
Oncogenic Ras

AbstractRas proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ∼ 25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanism-based therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer.

The Hox gene lin-39 is required during C. elegans vulval induction to select the outcome of Ras signaling

Development ◽  
1998 ◽  
Vol 125 (2) ◽  
pp. 181-190 ◽  
Author(s):  
J.N. Maloof ◽  
C. Kenyon
Keyword(s):  
Body Region ◽  
Ras Signaling ◽  
Cell Fates ◽  
Vulval Development ◽  
Ras Pathway ◽  
Hox Gene ◽  
C Elegans ◽  
Cell Divisions ◽  
Ras Activation ◽  
Vulval Precursor Cells

The Ras signaling pathway specifies a variety of cell fates in many organisms. However, little is known about the genes that function downstream of the conserved signaling cassette, or what imparts the specificity necessary to cause Ras activation to trigger different responses in different tissues. In C. elegans, activation of the Ras pathway induces cells in the central body region to generate the vulva. Vulval induction takes place in the domain of the Hox gene lin-39. We have found that lin-39 is absolutely required for Ras signaling to induce vulval development. During vulval induction, the Ras pathway, together with basal lin-39 activity, up-regulates lin-39 expression in vulval precursor cells. We find that if lin-39 function is absent at this time, no vulval cell divisions occur. Furthermore, if lin-39 is replaced with the posterior Hox gene mab-5, then posterior structures are induced instead of a vulva. Our findings suggest that in addition to permitting vulval cell divisions to occur, lin-39 is also required to specify the outcome of Ras signaling by selectively activating vulva-specific genes.

scholarly journals A quantitative systems pharmacology analysis of KRAS G12C covalent inhibitors

2017 ◽  
Author(s):  
Edward C. Stites ◽  
Andrey S. Shaw
Keyword(s):  
Human Cancer ◽  
Conventional Wisdom ◽  
Ras Signaling ◽  
Systems Pharmacology ◽  
Ras Pathway ◽  
Ras Protein ◽  
Oncogenic Mutation ◽  
Ras Activation ◽  
Covalent Inhibitors ◽  
Computational Systems

AbstractThe KRAS oncogene is the most common, activating, oncogenic mutation in human cancer. KRAS has proven difficult to target effectively. Two different strategies have recently been described for covalently targeting the most common activating KRAS mutant in lung cancer, KRAS G12C. Previously, we have developed a computational model of the processes that regulate Ras activation and this model has proven useful for understanding the complex behaviors of Ras signaling. Here, we use this model to perform a computational systems pharmacology analysis of KRAS G12C targeted covalent inhibitors. After updating our model to include Ras protein turnover, we verified the validity of our model for problems in this domain by comparing model behaviors with experimental behaviors. The model naturally reproduces previous experimental data, including several experimental observations that were interpreted as being contrary to conventional wisdom. Overall, this suggests that our model describes the Ras system well, including those areas where conventional wisdom struggles. We then used the model to investigate possible strategies to improve the ability of KRAS G12C inhibitors to inhibit Ras pathway signaling. We identify one, as of yet unexplored mechanism, that, if optimized, could improve the effectiveness of one class of KRAS inhibitor. We also simulated resistance to targeted therapies and found that resistance promoting mutations may reverse which class of KRAS G12C inhibitor inhibits the system better, suggesting that there may be value to pursuing both types of KRAS G12C inhibitors. Overall, this work demonstrates that systems biology approaches can provide insights that inform the drug development process.

scholarly journals CUX1 Deficiency Potentiates RAS Signaling to Drive Malignancy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1159-1159
Author(s):  
Ningfei An ◽  
Molly K Imgruet ◽  
Saira Khan ◽  
Lia Jueng ◽  
Sandeep Gurbuxani ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Genetic Interaction ◽  
Suppressor Gene ◽  
Ras Signaling ◽  
Hematopoietic Stem ◽  
Ras Pathway ◽  
Hematopoietic Malignancies ◽  
Oncogenic Ras ◽  
Myeloid Neoplasms ◽  
Pathway Activation

Abstract -7/del(7q) is prevalent in high-risk myeloid neoplasms and frequently co-occurs with gain-of-function mutations in the RAS pathway. Herein, we identify a genetic interaction between RAS and the 7q-encoded transcription factor, CUX1, that encompasses hematopoietic malignancies and solid-tumors. Mice with both oncogenic NrasG12D and Cux1 knockdown developed accelerated myeloid malignancies with leukemic transformation. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem/progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through reduction of negative regulators of RAS/PI3K signaling. Accordingly, NrasG12D;Cux1-knockdown HSPCs have heightened growth factor-sensitivity and downstream RAS pathway activation. Double mutant HSPCs were responsive to PIK3 or MEK inhibition. Similarly, low expression of CUX1 in primary AML samples correlates with sensitivity to the same inhibitors, suggesting a viable therapy for malignancies with CUX1 inactivation. This work demonstrates an unexpected convergence of an oncogene and tumor suppressor gene on the same pathway. Disclosures No relevant conflicts of interest to declare.

scholarly journals EGFRAP encodes a new negative regulator of the EGFR acting in both normal and oncogenic EGFR/Ras-driven tissue morphogenesis

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009738
Author(s):  
Jennifer Soler Beatty ◽  
Cristina Molnar ◽  
Carlos M. Luque ◽  
Jose F. de Celis ◽  
María D. Martín-Bermudo
Keyword(s):  
Imaginal Disc ◽  
Feedback Loop ◽  
Notch Pathway ◽  
Sh2 Domain ◽  
Negative Regulator ◽  
Ras Signaling ◽  
Ras Pathway ◽  
Phosphorylated Form ◽  
Ras Activation ◽  
Surveillance Mechanism

Activation of Ras signaling occurs in ~30% of human cancers. However, activated Ras alone is insufficient to produce malignancy. Thus, it is imperative to identify those genes cooperating with activated Ras in driving tumoral growth. In this work, we have identified a novel EGFR inhibitor, which we have named EGFRAP, for EGFR adaptor protein. Elimination of EGFRAP potentiates activated Ras-induced overgrowth in the Drosophila wing imaginal disc. We show that EGFRAP interacts physically with the phosphorylated form of EGFR via its SH2 domain. EGFRAP is expressed at high levels in regions of maximal EGFR/Ras pathway activity, such as at the presumptive wing margin. In addition, EGFRAP expression is up-regulated in conditions of oncogenic EGFR/Ras activation. Normal and oncogenic EGFR/Ras-mediated upregulation of EGRAP levels depend on the Notch pathway. We also find that elimination of EGFRAP does not affect overall organogenesis or viability. However, simultaneous downregulation of EGFRAP and its ortholog PVRAP results in defects associated with increased EGFR function. Based on these results, we propose that EGFRAP is a new negative regulator of the EGFR/Ras pathway, which, while being required redundantly for normal morphogenesis, behaves as an important modulator of EGFR/Ras-driven tissue hyperplasia. We suggest that the ability of EGFRAP to functionally inhibit the EGFR pathway in oncogenic cells results from the activation of a feedback loop leading to increase EGFRAP expression. This could act as a surveillance mechanism to prevent excessive EGFR activity and uncontrolled cell growth.

scholarly journals A Systems Mechanism for KRAS Mutant Allele Specific Responses to Targeted Therapy

2018 ◽  
Author(s):  
Thomas McFall ◽  
Jolene K Diedrich ◽  
Meron Mengistu ◽  
Stacy L Littlechild ◽  
Kendra V Paskvan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Genomic Medicine ◽  
Interaction Strength ◽  
Ras Signaling ◽  
Wild Type ◽  
Kras Mutations ◽  
Ras Pathway ◽  
Egfr Inhibition ◽  
Ras Activation ◽  
Allele Specific

A well-established genotype to phenotype relationship in genomic medicine is that activating KRAS mutations indicate resistance to anti-EGFR agents. We used a computational model of Ras signaling to investigate a confusing exception to this relationship whereby colorectal cancers with one specific, constitutively-active, mutant, KRAS G13D, respond to anti-EGFR agents. Our computational simulations of the biochemical processes that regulate Ras suggest EGFR inhibition reduces wild-type Ras activation in KRAS G13D mutant cancer cells more than in other KRAS mutant cancer cells. The model also reveals a non-intuitive, mutant-specific, dependency of wild-type Ras activation on EGFR. This dependency is determined by the interaction strength between a KRAS mutant and tumor suppressor neurofibromin. Our prospective experiments confirm this mechanism that arises from the systems-level regulation of Ras pathway signaling. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine.

scholarly journals Alin-45 rafEnhancer Screen Identifieseor-1,eor-2and Unusual Alleles of Ras Pathway Genes inCaenorhabditis elegans

Genetics ◽  
2002 ◽  
Vol 161 (1) ◽  
pp. 121-131 ◽  
Author(s):  
Christian E Rocheleau ◽  
Robyn M Howard ◽  
Alissa P Goldman ◽  
Mandy L Volk ◽  
Laura J Girard ◽  
...  
Keyword(s):  
Cell Fate ◽  
System Development ◽  
Phosphorylation Site ◽  
Egg Laying ◽  
Excretory System ◽  
Temperature Sensitive ◽  
Ras Signaling ◽  
Multiple Alleles ◽  
Ras Pathway ◽  
Fate Specification

AbstractIn Caenorhabditis elegans, the Ras/Raf/MEK/ERK signal transduction pathway controls multiple processes including excretory system development, P12 fate specification, and vulval cell fate specification. To identify positive regulators of Ras signaling, we conducted a genetic screen for mutations that enhance the excretory system and egg-laying defects of hypomorphic lin-45 raf mutants. This screen identified unusual alleles of several known Ras pathway genes, including a mutation removing the second SH3 domain of the sem-5/Grb2 adaptor, a temperature-sensitive mutation in the helical hairpin of let-341/Sos, a gain-of-function mutation affecting a potential phosphorylation site of the lin-1 Ets domain transcription factor, a dominantnegative allele of ksr-1, and hypomorphic alleles of sur-6/PP2A-B, sur-2/Mediator, and lin-25. In addition, this screen identified multiple alleles of two newly identified genes, eor-1 and eor-2, that play a relatively weak role in vulval fate specification but positively regulate Ras signaling during excretory system development and P12 fate specification. The spectrum of identified mutations argues strongly for the specificity of the enhancer screen and for a close involvement of eor-1 and eor-2 in Ras signaling.

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 Role of thyroid hormone-integrin αvβ3-signal and therapeutic strategies in colorectal cancers

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Yu-Chen S. H. Yang ◽  
Po-Jui Ko ◽  
Yi-Shin Pan ◽  
Hung-Yun Lin ◽  
Jacqueline Whang-Peng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cancer Cell ◽  
Growth Factor Receptor ◽  
Integrin Αvβ3 ◽  
Ras Signaling ◽  
Structural Protein ◽  
Cancer Cell Growth ◽  
Ras Pathway ◽  
Extracellular Signal ◽  
Cell Progression

AbstractThyroid hormone analogues—particularly, l-thyroxine (T4) has been shown to be relevant to the functions of a variety of cancers. Integrin αvβ3 is a plasma membrane structural protein linked to signal transduction pathways that are critical to cancer cell proliferation and metastasis. Thyroid hormones, T4 and to a less extend T3 bind cell surface integrin αvβ3, to stimulate the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway to stimulate cancer cell growth. Thyroid hormone analogues also engage in crosstalk with the epidermal growth factor receptor (EGFR)-Ras pathway. EGFR signal generation and, downstream, transduction of Ras/Raf pathway signals contribute importantly to tumor cell progression. Mutated Ras oncogenes contribute to chemoresistance in colorectal carcinoma (CRC); chemoresistance may depend in part on the activity of ERK1/2 pathway. In this review, we evaluate the contribution of thyroxine interacting with integrin αvβ3 and crosstalking with EGFR/Ras signaling pathway non-genomically in CRC proliferation. Tetraiodothyroacetic acid (tetrac), the deaminated analogue of T4, and its nano-derivative, NDAT, have anticancer functions, with effectiveness against CRC and other tumors. In Ras-mutant CRC cells, tetrac derivatives may overcome chemoresistance to other drugs via actions initiated at integrin αvβ3 and involving, downstream, the EGFR-Ras signaling pathways.

Accumulation of high level of pp60c-srcN is an early event during GM3-antibody mediated differentiation of neuro-2a neuroblastoma cells

1993 ◽  
Vol 625 (2) ◽  
pp. 197-202 ◽  
Author(s):  
M. Chakraborty ◽  
G.M. Anderson ◽  
A. Chakraborty ◽  
D. Chatterjee
Keyword(s):  
Neuroblastoma Cells ◽  
Early Event ◽  
High Level
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