Pharmacologically inhibiting BRAF/ERK and CDK4 restores APCFZR1 E3 ligase activity. Pharmacologically inhibiting BRAF/ERK and CDK4 restores APCFZR1 E3.

Slides:

Advertisements

Similar presentations

Date of download: 9/17/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Differential Responses of Human Papillary Thyroid.

Advertisements

Copyright © 2007 American Medical Association. All rights reserved.

RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export Gaurav Pathria, Bhavuk Garg, Christine Wagner, Kanika Garg, Melanie.

CDK2 is highly expressed in colon cancer cells and curcumin selectively suppresses HCT116 cell proliferation. CDK2 is highly expressed in colon cancer.

MAPK pathway inhibitors.

Genetic alterations in the PI3K–PTEN–AKT pathway detected during disease progression and their functional impacts. Genetic alterations in the PI3K–PTEN–AKT.

HDAC3 regulates AKT phosphorylation

PI3K isoform–selective inhibitors and PTEN induction decrease ERK phosphorylation. PI3K isoform–selective inhibitors and PTEN induction decrease ERK phosphorylation.

Small-molecule inhibitor QLT-0267 suppresses ILK activity and inhibits its downstream signaling. Small-molecule inhibitor QLT-0267 suppresses ILK activity.

Figure 4 Possible combination therapies CDK4/6 inhibitors

Volume 33, Issue 2, Pages (January 2009)

RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export Gaurav Pathria, Bhavuk Garg, Christine Wagner, Kanika Garg, Melanie.

DEPTOR, an mTOR Inhibitor, Is a Physiological Substrate of SCFβTrCP E3 Ubiquitin Ligase and Regulates Survival and Autophagy Yongchao Zhao, Xiufang Xiong,

Altered interferon signaling with JAK1 loss-of-function mutation in M431 and interferon gamma-inducible PD-L1 expression by 48 melanoma cell lines. Altered.

Combined inhibition of MAP kinase and KIT signaling destabilizes ETV1 protein and results in enhanced growth suppression of human GIST cells. Combined.

Proline supplementation during P5CS protein knockdown suppressed GCN2 activation. Proline supplementation during P5CS protein knockdown suppressed GCN2.

Reduction of Sca-1 increases PPARγ expression.

APCFZR1 promotes BRAF ubiquitination in a D-box–dependent manner.

Kavitha Gowrishankar, Stephanie Snoyman, Gulietta M. Pupo, Therese M

Ganglioside GM3 Promotes Carcinoma Cell Proliferation via Urokinase Plasminogen Activator-Induced Extracellular Signal-Regulated Kinase-Independent p70S6.

MiTF Regulates Cellular Response to Reactive Oxygen Species through Transcriptional Regulation of APE-1/Ref-1 Feng Liu, Yan Fu, Frank L. Meyskens Journal.

RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma

The EGF receptor confers BRAF inhibitor resistance in BRAF-mutant melanoma cells. The EGF receptor confers BRAF inhibitor resistance in BRAF-mutant melanoma.

Regulated P124SMEK1 expression cannot alter p-ERK levels or sensitivity to BRAF or MEK inhibition in V600EBRAF melanoma cell lines. Regulated P124SMEK1.

A genome-wide RNAi pooled screen identifies NF1 as a key determinant of RAF inhibitor sensitivity in melanoma cells. A genome-wide RNAi pooled screen identifies.

Signaling induced by BRAF L597R and L597S is sensitive to BRAF and MEK inhibitors. Signaling induced by BRAF L597R and L597S is sensitive to BRAF and MEK.

Volume 4, Issue 4, Pages (August 2013)

NF-κB1/p105 Regulates Lipopolysaccharide-Stimulated MAP Kinase Signaling by Governing the Stability and Function of the Tpl2 Kinase Michael R. Waterfield,

Volume 59, Issue 6, Pages (September 2015)

BRAF inhibitor-resistant BRAF-mutant melanoma cells show increased invasion and metastatic potential. BRAF inhibitor-resistant BRAF-mutant melanoma cells.

Role of HER2 in mediating acquired resistance to EGFR inhibition.

Rsk1 mediates a MEK–MAP kinase cell survival signal

AMPK induces VEGF-A production by upregulating ERK signaling.

MEKi-induced RTK changes are consistent with decreased proteolytic receptor shedding. MEKi-induced RTK changes are consistent with decreased proteolytic.

AML cells display differential sensitivity to inhibition of IKBKE and TBK1. AML cells display differential sensitivity to inhibition of IKBKE and TBK1.

CEP55 is a downstream effector of MAPK signaling

Volume 22, Issue 5, Pages (November 2012)

Mutant BRAF Melanomas—Dependence and Resistance

Aβ-mediated Ras-MAPK signaling and Cyclin D1 expression in B103 cells are dependent on APP expression and can be reversed with MEK or Ras inhibition. Aβ-mediated.

MEL23 and MEL24 inhibit Mdm2 and p53 ubiquitination through the Mdm2-MdmX hetero-complex. MEL23 and MEL24 inhibit Mdm2 and p53 ubiquitination through the.

Gramicidin A (GA) decreases HIF protein expression in RCC cells.

Induction of CDCP1 is regulated by Ras in NSCLC cells.

The SFKs confer BRAF inhibitor resistance in BRAF-mutant melanoma cells. The SFKs confer BRAF inhibitor resistance in BRAF-mutant melanoma cells. A, phospho-protein.

Effect of LY on phosphorylation of various MAP kinase substrates in HeLa cells in vitro. Effect of LY on phosphorylation of various MAP kinase.

Inhibition of stress-associated MAPK signaling attenuates SASP expression in CAFs. A, N-CAFs were treated with 100 nmol/L GEM plus DMSO or the above-listed.

The effect of IAA on tumor growth in an SK-MEL-28 xenograft model.

The expression of d-GM3 facilitates melanoma cell migration and invasion by activating p38 MAPK, not ERK. A, cell migration and invasion in d-GM3–positive.

ONC201 activates an ISR, decreases cyclin D1 expression, and causes an accumulation of cells in G1 in TNBC cells sensitive to the compounds' antiproliferative.

The effect of IAA and glycyrrhizin (Gc) on growth of human melanoma cells. The effect of IAA and glycyrrhizin (Gc) on growth of human melanoma cells. A,

Ectopic expression of CA RSK1 mutant protects melanoma cells from PD98059-mediated apoptosis. Ectopic expression of CA RSK1 mutant protects melanoma cells.

Volume 44, Issue 2, Pages (October 2011)

IAA inhibits PI3K, MKK4, and MKK7 kinase activities by directly binding in an ATP-competitive manner. IAA inhibits PI3K, MKK4, and MKK7 kinase activities.

Identification of compounds that enhance TMZ cytotoxicity in melanoma cells by screening the Spectrum Collection library. Identification of compounds that.

Establishment of transcriptional class distinction in melanocytes.

MAPK/ERK signaling regulates TLR4 gene expression in response to BRAFV600E. MAPK/ERK signaling regulates TLR4 gene expression in response to BRAFV600E.

Pdcd4 expression inhibits AP-1 transactivation.

KRASG12D- and BRAFV600E-induced survival in PDECs requires IGF1R signaling. KRASG12D- and BRAFV600E-induced survival in PDECs requires IGF1R signaling.

Cell-cycle regulatory proteins were controlled by O-GlcNAc at FOXO3 S284 through MDM2. Cell-cycle regulatory proteins were controlled by O-GlcNAc at FOXO3.

Differential effects of the RAF inhibitor PLX4032 in BRAF-mutant melanoma, thyroid, and colorectal cancer cell lines. Differential effects of the RAF inhibitor.

Schematic representation of signaling pathways associated with cannabinoid receptor activation induced by its agonists. Schematic representation of signaling.

LY elicits hyperphosphorylation of Akt.

An overview of the MAPK signaling pathway with points of therapeutic intervention indicated. An overview of the MAPK signaling pathway with points of therapeutic.

Regulation of signaling by wild-type and oncogenic Ras.

Effect of SFN on the total activity and protein expression of HDACs in JB6 P+ cells. Effect of SFN on the total activity and protein expression of HDACs.

NSD2-mediated methylation of PTEN at K349 dictates cellular sensitivity to DNA-damaging agents. NSD2-mediated methylation of PTEN at K349 dictates cellular.

Inhibition of BCR-mediated signaling by ARQ 531.

I3C reduces the level of Cdc25A protein in breast cancer cells.

MEK1/2-ERK1/2-p190RHOGAP and INK4a/ARF deficiency drive RHOA activation in NSCLC. A and B, G-LISA assay showing RHOA-GTP levels in H460, A549, and H838.

AXL is not necessary for maintenance of intrinsic resistance.

Time course of NMT knockdown.

Presentation transcript:

Pharmacologically inhibiting BRAF/ERK and CDK4 restores APCFZR1 E3 ligase activity. Pharmacologically inhibiting BRAF/ERK and CDK4 restores APCFZR1 E3 ligase activity. A, Protein levels of BRAF and other APCFZR1 substrates decreased upon BRAFV600E and CDK4/6 inhibition in melanoma cells. IB analysis of BRAFV600E- and CDK4R24C-expressing SK-MEL-28 melanoma cells treated with either 1 μmol/L BRAFV600E inhibitor PLX4032 (V600Ei), 10 μmol/L pan-CDK inhibitor mimosine (pan-CDKi), 1 μmol/L CDK4/6 inhibitor PD0332991 (CDK4i), 1 μmol/L PLX4032 + 10 μmol/L mimosine, 1 μmol/L PLX4032 + 1 μmol/L PD0332991, or DMSO as a negative control for 24 hours before harvesting. BRAF band intensities were quantified using ImageJ, normalized to corresponding TUBULIN band intensities, and then normalized to DMSO control lane. B, Protein levels of BRAF and other APCFZR1 substrates reduced upon MEK and CDK4/6 inhibition in melanoma cells. IB analysis of BRAFWT-expressing HBL melanoma cells treated with either 1 μmol/L MEK inhibitor PD0325901 (MEKi), 10 μmol/L pan-CDK inhibitor mimosine (pan-CDKi), 1 μmol/L CDK4/6 inhibitor PD0332991 (CDK4i), 1 μmol/L PD0325901 + 10 μmol/L mimosine, 1 μmol/L PD0325901 + 1 μmol/L PD0332991 or DMSO as a negative control for 24 hours before harvesting. BRAF band intensities were quantified using ImageJ, normalized to corresponding TUBULIN band intensities, and then normalized to DMSO control lane. C, Depletion of FZR1 in BRAFV600E-inhibited melanoma cells led to the upregulation of BRAF and PLK1. IB analysis of BRAFV600E-expressing A375 melanoma cells, which were infected with the control (shScr) or the indicated shFZR1 lentiviral shRNA constructs. The infected cells were selected with 1 μg/mL puromycin for 72 hours to eliminate the noninfected cells before harvesting. Prior to the harvest, cells were treated with DMSO (as a negative control) or 1 μmol/L BRAFV600E inhibitor PLX4032 (V600Ei) for 24 hours as indicated. BRAF band intensities were quantified using ImageJ, normalized to corresponding TUBULIN band intensities, and then normalized to DMSO control lane (top row) or normalized to the shScr + V600Ei lane (bottom row). D, A schematic illustration of the proposed model for the putative role of FZR1 in suppressing BRAF dimerization–mediated transactivation of downstream MEK/ERK signaling to bypass PLX4032-triggered BRAFV600E inhibition in melanoma cells, as well as how mechanistically hyperactive ERK and/or CYCLIN D1/CDK4-mediated phosphorylation of FZR1 inhibits APCFZR1 E3 ligase activity in BRAFV600E melanoma cells. Lixin Wan et al. Cancer Discov 2017;7:424-441 ©2017 by American Association for Cancer Research