15-deoxy-Δ12,14-prostaglandin J2Down-Regulates Activin-Induced Activin Receptor, Smad, and Cytokines Expression via Suppression of NF-κB and MAPK Signaling in HepG2 Cells

15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) and activin are implicated in the control of apoptosis, cell proliferation, and inflammation in cells. We examined both the mechanism by which 15d-PGJ2regulates the transcription of activin-induced activin receptors (ActR) and Smads in HepG2 cells and the involvement of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in this regulation. Activin A (25 ng/mL) inhibited HepG2 cell proliferation, whereas 15d-PGJ2(2 μM and 5 μM) had no effect. Activin A and 15d-PGJ2showed different regulatory effects on ActR and Smad expression, NF-κB p65 activity and MEK/ERK phosphorylation, whereas they both decreased IL-6 production and increased IL-8 production. When co-stimulated with 15d-PGJ2and activin, 15d-PGJ2inhibited the activin-induced increases in ActR and Smad expression, and decreased activin-induced IL-6 production. However, it increased activin-induced IL-8 production. In addition, 15d-PGJ2inhibited activin-induced NF-κB p65 activity and activin-induced MEK/ERK phosphorylation. These results suggest that 15d-PGJ2suppresses activin-induced ActR and Smad expression, down-regulates IL-6 production, and up-regulates IL-8 production via suppression of NF-κB and MAPK signaling pathway in HepG2 cells. Regulation of ActR and Smad transcript expression and cytokine production involves NF-κB and the MAPK pathway via interaction with 15d-PGJ2/activin/Smad signaling.

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HGF promotes adhesion of ATP-depleted renal tubular epithelial cells in a MAPK-dependent manner

AJP Renal Physiology ◽

10.1152/ajprenal.2001.281.1.f62 ◽

2001 ◽

Vol 281 (1) ◽

pp. F62-F70 ◽

Cited By ~ 18

Author(s):

Zhen-Xiang Liu ◽

Christian H. Nickel ◽

Lloyd G. Cantley

Keyword(s):

Cell Adhesion ◽

Mapk Pathway ◽

Collecting Duct ◽

Mapk Signaling ◽

Atp Depletion ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Erk Phosphorylation ◽

Mitogen Activated Protein ◽

Renal Tubular

Hepatocyte growth factor (HGF) has been shown to enhance recovery from renal tubular ischemia. We investigated the possibility that HGF improves recovery by preventing ischemia-induced loss of cell adhesion. Murine inner medullary collecting duct-3 (mIMCD-3) cells subjected to 90% ATP depletion demonstrated a 55% decrease in adhesion, an effect that was completely reversed by the addition of HGF. Assays examining release of adherent cells revealed similar results with 30 min of ATP depletion causing loss of adhesion of 25% of mIMCD-3 cells and HGF completely reversing this effect. In contrast, HGF was unable to reverse the loss of adhesion of cells exposed to 99% ATP depletion. Examination of the mitogen-activated protein kinase (MAPK) signaling pathway revealed that HGF could induce extracellular signal-regulated kinase (ERK) phosphorylation in control and 90% ATP-depleted cells but not in 99% ATP-depleted cells. Inhibition of ERK activation with U0126 completely blocked the HGF-dependent reversal of ATP-depleted cell adhesion. Thus ATP-depleted cells demonstrate a marked decrease in cell adhesion that is reversible by the addition of HGF. This effect of HGF requires activation of the MAPK pathway.

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Ghrelin exerts a proliferative effect on a rat pituitary somatotroph cell line via the mitogen-activated protein kinase pathway

Acta Endocrinologica ◽

10.1530/eje.0.1510233 ◽

2004 ◽

pp. 233-240 ◽

Cited By ~ 99

Author(s):

AM Nanzer ◽

S Khalaf ◽

AM Mozid ◽

RC Fowkes ◽

MV Patel ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Cell Line ◽

Kinase Inhibitor ◽

Thymidine Incorporation ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Gh3 Cells ◽

Rat Pituitary ◽

Mitogen Activated Protein

OBJECTIVES: Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities and a widespread tissue distribution. Ghrelin is the endogenous ligand of the GH secretagogue receptor type 1a (GHS-R1a), and both ghrelin and the GHS-R1a are expressed in the pituitary. There are conflicting data regarding the effects of ghrelin on cell proliferation. A positive effect on proliferation and activation of the mitogen-activated protein kinase (MAPK) pathway has been found in hepatoma, adipose, cardiomyocyte and prostate cell lines. However, ghrelin has also been shown to have anti-proliferative effects on breast, lung and thyroid cell lines. We therefore examined the effect of ghrelin on the rat pituitary cell line GH3. METHODS: RT-PCR was used for the detection of GHS-R1a and pre-proghrelin mRNA expression in GH3 cells. The effect of ghrelin on cell proliferation was studied using [(3)H]thymidine incorporation; cell counting and the activation of the MAPK pathway were studied using immunoblotting and inhibitors of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinase C (PKC) and tyrosine phosphatase pathways. RESULTS: GHS-R1a and ghrelin mRNA expression were detected in GH3 cells. Ghrelin, at 10(-10) to 10(-6) M concentrations, significantly increased [(3)H]thymidine incorporation (at 10(-9) M, 183+/-13% (means+/-s.e.m.) compared with untreated controls), while 12-phorbol 13-myristate acetate (PMA) at 10(-7) M (used as a positive control) caused a 212+/-14% increase. A reproducible stimulatory effect of desoctanoyl ghrelin was also observed on [(3)H]thymidine incorporation (135+/-5%; P<0.01 at 10(-9) M compared with control), as well as on the cell count (control 6.8 x 10(4)+/-8.7 x 10(3) cells/ml vs desoctanoyl ghrelin (10(-9) M) 1.04 x 10(5)+/-7.5 x 10(3) cells/ml; P<0.01). Ghrelin caused a significant increase in phosphorylated ERK 1/2 in immunoblotting, while desoctanoyl ghrelin showed a smaller but also significant stimulatory effect. The positive effect of ghrelin and desoctanoyl ghrelin on [(3)H]thymidine incorporation was abolished by the MAPK kinase inhibitor U0126, the PKC inhibitor GF109203X and the tyrosine kinase inhibitor tyrphostin 23, suggesting that the ghrelin-induced cell proliferation of GH3 cells is mediated both via a PKC-MAPK-dependent pathway and via a tyrosine kinase-dependent pathway. This could also be clearly demonstrated by Western blot analysis, where a transient increase in ERK 1/2 phosphorylation by ghrelin was attenuated by all three inhibitors. CONCLUSION: We have shown a novel role for ghrelin in stimulating the proliferation of a somatotroph pituitary tumour cell line, suggesting that ERK activation is involved in mediating the effects of ghrelin on cell proliferation. Desoctanoyl ghrelin showed a similar effect. As ghrelin has been shown to be expressed in both normal and adenomatous pituitary tissue, locally produced ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway.

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APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00427.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. E103-E110 ◽

Cited By ~ 59

Author(s):

Xiaoban Xin ◽

Lijun Zhou ◽

Caleb M. Reyes ◽

Feng Liu ◽

Lily Q. Dong

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Mapk Pathway ◽

Adaptor Protein ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Scaffolding Protein ◽

Mapk Activation ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-β-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.

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Phosphorylation of Msx1 promotes cell proliferation through the Fgf9/18-MAPK signaling pathway during embryonic limb development

Nucleic Acids Research ◽

10.1093/nar/gkaa905 ◽

2020 ◽

Vol 48 (20) ◽

pp. 11452-11467

Author(s):

Yenan Yang ◽

Xiaoli Zhu ◽

Xiang Jia ◽

Wanwan Hou ◽

Guoqiang Zhou ◽

...

Keyword(s):

Cell Proliferation ◽

Limb Development ◽

Early Stage ◽

Control Cell ◽

Cell Lineage ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Embryonic Limb ◽

Underlying Mechanisms

Abstract Msh homeobox (Msx) is a subclass of homeobox transcriptional regulators that control cell lineage development, including the early stage of vertebrate limb development, although the underlying mechanisms are not clear. Here, we demonstrate that Msx1 promotes the proliferation of myoblasts and mesenchymal stem cells (MSCs) by enhancing mitogen-activated protein kinase (MAPK) signaling. Msx1 directly binds to and upregulates the expression of fibroblast growth factor 9 (Fgf9) and Fgf18. Accordingly, knockdown or antibody neutralization of Fgf9/18 inhibits Msx1-activated extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Mechanistically, we determined that the phosphorylation of Msx1 at Ser136 is critical for enhancing Fgf9 and Fgf18 expression and cell proliferation, and cyclin-dependent kinase 1 (CDK1) is apparently responsible for Ser136 phosphorylation. Furthermore, mesenchymal deletion of Msx1/2 results in decreased Fgf9 and Fgf18 expression and Erk1/2 phosphorylation, which leads to serious defects in limb development in mice. Collectively, our findings established an important function of the Msx1-Fgf-MAPK signaling axis in promoting cell proliferation, thus providing a new mechanistic insight into limb development.

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miR-19 Promotes Cell Proliferation, Invasion, Migration, and EMT by Inhibiting SPRED2-mediated Autophagy in Osteosarcoma Cells

Cell Transplantation ◽

10.1177/0963689720962460 ◽

2020 ◽

Vol 29 ◽

pp. 096368972096246

Author(s):

Chuhai Xie ◽

Shengyao Liu ◽

Boyi Wu ◽

Yu Zhao ◽

Binwei Chen ◽

...

Keyword(s):

Cell Proliferation ◽

Mapk Pathway ◽

Biological Effects ◽

Rapid Development ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Luciferase Reporter ◽

Osteosarcoma Cells ◽

Mesenchymal Transition ◽

Erk Mapk

Osteosarcoma is an aggressive malignancy with rapid development and poor prognosis. microRNA-19 (miR-19) plays an important role in several biological processes. Sprouty-related EVH1 domain protein 2 (SPRED2) is a suppressor of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling to inhibit tumor development and progression by promoting autophagy. In this study, we investigated the roles of miR-19, SPRED2, and autophagy in osteosarcoma. We detected the expression of miR-19, SPRED2, epithelial–mesenchymal transition (EMT) markers, and autophagy-related proteins via quantitative real-time polymerase chain reaction or western blot. To evaluate the function of miR-19 and SPRED2, we used MTT and colony formation assays to detect cell proliferation, Transwell, and wound-healing assays to detect cell invasion and migration. Targetscan and luciferase reporter assays confirmed the relationship between SPRED2 and miR-19. The expression of miR-19 was significantly upregulated in osteosarcoma, while SPRED2 was downregulated. miR-19 inhibitor reduced cell proliferation, invasion, migration, and EMT, while its cell biological effects were partially reversed by addition of autophagy inhibitor 3-methyladenine (3-MA) or SPRED2 siRNA in osteosarcoma. SPRED2, a suppressor of ERK/MAPK pathway that is known to trigger autophagy, was identified as a direct target of miR-19. SPRED2 overexpression increased cell proliferation, invasion, migration, and EMT by promoting autophagy, and the effects could be inhibited by 3-MA. Collectively, these findings reveal an underlying mechanism for development of osteosarcoma. miR-19 was upregulated in osteosarcoma cells, and negatively regulated SPRED2, thus promoting the malignant transformation of osteosarcoma cells via inhibiting SPRED2-induced autophagy. Therefore, miR-19/SPRED2 may be a potential target for the treatment of osteosarcoma.

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Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

Molecular and Cellular Biology ◽

10.1128/mcb.24.3.1081-1095.2004 ◽

2004 ◽

Vol 24 (3) ◽

pp. 1081-1095 ◽

Cited By ~ 101

Author(s):

Nicole H. Purcell ◽

Dina Darwis ◽

Orlando F. Bueno ◽

Judith M. Müller ◽

Roland Schüle ◽

...

Keyword(s):

Mammalian Cells ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Erk Signaling ◽

Interacting Protein ◽

Hypertrophic Response ◽

Extracellular Signal ◽

Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.

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The Rho1p Exchange Factor Rgf1p Signals Upstream from the Pmk1 Mitogen-activated Protein Kinase Pathway in Fission Yeast

Molecular Biology of the Cell ◽

10.1091/mbc.e08-07-0673 ◽

2009 ◽

Vol 20 (2) ◽

pp. 721-731 ◽

Cited By ~ 20

Author(s):

Patricia Garcia ◽

Virginia Tajadura ◽

Yolanda Sanchez

Keyword(s):

Mapk Pathway ◽

Osmotic Shock ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Cell Integrity ◽

Actin Reorganization ◽

Exchange Factor ◽

Mitogen Activated Protein ◽

Chlorine Ion ◽

Kinase Pathway

The Schizosaccharomyces pombe exchange factor Rgf1p specifically regulates Rho1p during polarized growth. Rgf1p activates the β-glucan synthase (GS) complex containing the catalytic subunit Bgs4p and is involved in the activation of growth at the second end, a transition that requires actin reorganization. In this work, we investigated Rgf1p signaling and observed that Rgf1p acted upstream from the Pck2p-Pmk1p MAPK signaling pathway. We noted that Rgf1p and calcineurin play antagonistic roles in Cl− homeostasis; rgf1Δ cells showed the vic phenotype (viable in the presence of immunosuppressant and chlorine ion) and were unable to grow in the presence of high salt concentrations, both phenotypes being characteristic of knockouts of the MAPK components. In addition, mutations that perturb signaling through the MAPK pathway resulted in defective cell integrity (hypersensitivity to caspofungin and β-glucanase). Rgf1p acts by positively regulating a subset of stimuli toward the Pmk1p-cell integrity pathway. After osmotic shock and cell wall damage HA-tagged Pmk1p was phosphorylated in wild-type cells but not in rgf1Δ cells. Finally, we provide evidence to show that Rgf1p regulates Pmk1p activation in a process that involves the activation of Rho1p and Pck2p, and we demonstrate that Rgf1p is unique in this signaling process, because Pmk1p activation was largely independent of the other two Rho1p-specific GEFs, Rgf2p and Rgf3p.

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Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution® Screen

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057106287136 ◽

2006 ◽

Vol 11 (4) ◽

pp. 423-434 ◽

Cited By ~ 12

Author(s):

Charlotta Grånäs ◽

Betina Kerstin Lundholt ◽

Frosty Loechel ◽

Hans-Christian Pedersen ◽

Sara Petersen Bjørn ◽

...

Keyword(s):

Protein Kinase ◽

Signaling Pathway ◽

Kinase Inhibitors ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

A Cell ◽

Protein Kinase Signaling

The RAS-mitogen-activated protein kinase (MAPK) signaling pathway has a central role in regulating the proliferation and survival of both normal and tumor cells. This pathway has been 1 focus area for the development of anticancer drugs, resulting in several compounds, primarily kinase inhibitors, in clinical testing. The authors have undertaken a cell-based, high-throughput screen using a novel ERF1 Redistribution® assay to identify compounds that modulate the signaling pathway. The hit compounds were subsequently tested for activity in a functional cell proliferation assay designed to selectively detect compounds inhibiting the proliferation of MAPK pathway-dependent cancer cells. The authors report the identification of 2 cell membrane-permeable compounds that exhibit activity in the ERF1 Redistribution® assay and selectively inhibit proliferation of MAPK pathway-dependent malignant melanoma cells at similar potencies (IC50 =< 5 μM). These compounds have drug-like structures and are negative in RAF, MEK, and ERK in vitro kinase assays. Drugs belonging to these compound classes may prove useful for treating cancers caused by excessive MAPK pathway signaling. The results also show that cell-based, high-content Redistribution® screens can detect compounds with different modes of action and reveal novel targets in a pathway known to be disease relevant.

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Comparative Analysis of Transmembrane Regulators of the Filamentous Growth Mitogen-Activated Protein Kinase Pathway Uncovers Functional and Regulatory Differences

Eukaryotic Cell ◽

10.1128/ec.00085-15 ◽

2015 ◽

Vol 14 (9) ◽

pp. 868-883 ◽

Cited By ~ 5

Author(s):

Hema Adhikari ◽

Lauren M. Caccamise ◽

Tanaya Pande ◽

Paul J. Cullen

Keyword(s):

Protein Kinase ◽

Mapk Pathway ◽

Filamentous Growth ◽

Mapk Signaling ◽

Fine Tuning ◽

Mitogen Activated Protein Kinase ◽

Rate Limiting Step ◽

Mitogen Activated Protein ◽

Multiple Signaling ◽

Growth Pathway

ABSTRACTFilamentous growth is a microbial differentiation response that involves the concerted action of multiple signaling pathways. In budding yeast, one pathway that regulates filamentous growth is a Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway. Several transmembrane (TM) proteins regulate the filamentous growth pathway, including the signaling mucin Msb2p, the tetraspan osmosensor Sho1p, and an adaptor Opy2p. The TM proteins were compared to identify common and unique features. Msb2p, Sho1p, and Opy2p associated by coimmunoprecipitation analysis but showed predominantly different localization patterns. The different localization patterns of the proteins resulted in part from different rates of turnover from the plasma membrane (PM). In particular, Msb2p (and Opy2p) were turned over rapidly compared to Sho1p. Msb2p signaled from the PM, and its turnover was a rate-limiting step in MAPK signaling. Genetic analysis identified unique phenotypes of cells overexpressing the TM proteins. Therefore, each TM regulator of the filamentous growth pathway has its own regulatory pattern and specific function in regulating filamentous growth. This specialization may be important for fine-tuning and potentially diversifying the filamentation response.

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Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

10.1101/231142 ◽

2017 ◽

Cited By ~ 2

Author(s):

Helma Zecena ◽

Daniel Tveit ◽

Zi Wang ◽

Ahmed Farhat ◽

Parvita Panchal ◽

...

Keyword(s):

Malignant Melanoma ◽

Mapk Pathway ◽

Treatment Resistance ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Cellular Model ◽

Braf Mutations ◽

Mitogen Activated Protein ◽

Inhibitor Resistance ◽

Mapk Inhibitor

AbstractKinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. The cellular model evolved in response to clinical dosage of BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring based on non-genomic adaptation was validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Downregulation of tumor suppressors and negative MAPK regulators, dual specific phosphatases, reengages mitogenic signaling. Upregulation of growth factors or cytokine receptors triggers signaling pathways circumventing BRAF blockage. Changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, an upregulation of pigmentation in inhibitor resistant melanoma cells was observed. Cellular pathways utilized during inhibitor resistance promoted melanogenesis, a pathway which partially overlaps with MAPK signaling. Upstream regulator analysis suggested gene expression changes of forkhead box and hypoxia inducible factor family transcription factors. The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy resistant cancer.

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