HER2 stabilizes survivin while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage

2013 ◽  
Vol 451 (1) ◽  
pp. 123-134 ◽  
Author(s):  
Ji-hyun Ju ◽  
Wonseok Yang ◽  
Sunhwa Oh ◽  
KeeSoo Nam ◽  
Kyung-min Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Fate ◽  
Target Genes ◽  
Growth Factor Receptor ◽  
Cyclin B1 ◽  
Notch Signalling ◽  
Her2 Overexpression ◽  
Cell Fate Decisions ◽  
Notch Intracellular Domain ◽  
Notch Cleavage

In breast cancer, the HER2 (human epidermal growth factor receptor 2) receptor tyrosine kinase is associated with extremely poor prognosis and survival. Notch signalling has a key role in cell-fate decisions, especially in cancer-initiating cells. The Notch intracellular domain produced by Notch cleavage is translocated to the nucleus where it activates transcription of target genes. To determine the combinatory effect of HER2 and Notch signalling in breast cancer, we investigated the effect of HER2 on Notch-induced cellular phenomena. We found the down-regulation of Notch-dependent transcriptional activity by HER2 overexpression. Also, the HER2/ERK (extracellular-signal-regulated kinase) signal pathway down-regulated the activity of γ-secretase. When we examined the protein level of Notch target genes in HER2-overexpressing cells, we observed that the level of survivin, downstream of Notch, increased in HER2 cells. We found that activation of ERK resulted in a decrease in XAF1 [XIAP (X-linked inhibitor of apoptosis)-associated factor 1] which reduced the formation of the XIAP–XAF1 E3 ligase complex to ubiquitinate survivin. In addition, Thr34 of survivin was shown to be the most important residue in determining survivin stability upon phosphorylation after HER2/Akt/CDK1 (cyclin-dependent kinase 1)–cyclin B1 signalling. The results of the present study show the combinatorial effects of HER2 and Notch during breast oncogenesis.

SUMOylated Non-canonical Polycomb PRC1.6 Complex as a Prerequisite for Recruitment of Transcription Factor RBPJ

2021 ◽  
Author(s):  
Małgorzata Sotomska ◽  
Robert Liefke ◽  
Francesca Ferrante ◽  
Heiko Schwederski ◽  
Franz Oswald ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Target Gene ◽  
Target Genes ◽  
Adult Stem Cell ◽  
Notch Signalling ◽  
Cell Fate Decisions ◽  
Contact Points ◽  
Coactivator Complex

Abstract BackgroundNotch signaling controls cell fate decisions in many contexts during development and adult stem cell homeostasis and, when dysregulated, leads to carcinogenesis. The central transcription factor RBPJ assembles the Notch coactivator complex in the presence of Notch signalling, and represses Notch target gene expression in its absence.ResultsWe identified L3MBTL2 and additional members of the non-canonical polycomb repressive PRC1.6 complex in DNA-bound RBPJ associated complexes and demonstrate that L3MBTL2 directly interacts with RBPJ. Depletion of RBPJ does not affect occupancy of PRC1.6 components at Notch target genes. Conversely, absence of L3MBTL2 reduces RBPJ occupancy at enhancers of Notch target genes. Since L3MBTL2 and additional members of the PRC1.6 are known to be SUMOylated, we investigated whether RBPJ uses SUMO-moieties as contact points. Indeed, we found that RBPJ binds to SUMO2/3 and that this interaction depends on a defined SUMO-interaction motif. Furthermore, we show that pharmacological inhibition of SUMOylation reduces RBPJ occupancy at Notch target genes.ConclusionsWe propose that the PRC1.6 complex and its conjugated SUMO-modifications provide a scaffold that is recognized by RBPJ and promotes its recruitment to Notch target genes.

The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder

2008 ◽  
Vol 36 (2) ◽  
pp. 157-166 ◽  
Author(s):  
Angela Bertagna ◽  
Dima Toptygin ◽  
Ludwig Brand ◽  
Doug Barrick
Keyword(s):  
Cell Fate ◽  
Tertiary Structure ◽  
Transmembrane Protein ◽  
Notch Signalling ◽  
Chain Model ◽  
Intracellular Domain ◽  
Cell Fate Decisions ◽  
Notch Intracellular Domain ◽  
Binding Regions ◽  
The Impact

Cell-fate decisions in metazoans are frequently guided by the Notch signalling pathway. Notch signalling is orchestrated by a type-1 transmembrane protein, which, upon interacting with extracellular ligands, is proteolytically cleaved to liberate a large intracellular domain [NICD (Notch intracellular domain)]. NICD enters the nucleus where it binds the transcription factor CSL (CBF1/suppressor of Hairless/Lag-1) and activates transcription of Notch-responsive genes. In the present paper, the interaction between the Drosophila NICD and CSL will be examined. This interaction involves two separate binding regions on NICD: the N-terminal tip of NICD {the RAM [RBP-Jκ (recombination signal-binding protein 1 for Jκ)-associated molecule] region} and an ankyrin domain ∼100 residues away. CD studies show that the RAM region of NICD lacks α-helical and β-sheet secondary structure, and also lacks rigid tertiary structure. Fluorescence studies show that the tryptophan residues in RAM are highly solvated and are quenched by solvent. To assess the impact of this apparent disorder on the bivalent binding of NICD to CSL, we modelled the region between the RAM and ANK (ankyrin repeat)-binding regions using polymer statistics. A WLC (wormlike chain) model shows that the most probable sequence separation between the two binding regions is ∼50 Å (1 Å=0.1 nm), matching the separation between these two sites in the complex. The WLC model predicts a substantial enhancement of ANK occupancy via effective concentration, and suggests that the linker length between the two binding regions is optimal for bivalent interaction.

scholarly journals Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

2014 ◽  
Vol 8 ◽  
pp. BCBCR.S9453 ◽  
Author(s):  
Adam M. Brufsky
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Intrinsic Resistance ◽  
Her2 Positive

Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancers; HER2 overexpression is indicative of poor prognosis. Trastuzumab, an anti-HER2 monoclonal antibody, has led to improved outcomes in patients with HER2-positive breast cancer, including improved overall survival in adjuvant and first-line settings. However, a large proportion of patients with breast cancer have intrinsic resistance to HER2-targeted therapies, and nearly all become resistant to therapy after initial response. Elucidation of underlying mechanisms contributing to HER2 resistance has led to development of novel therapeutic strategies, including those targeting HER2 and downstream pathways, heat shock protein 90, telomerase, and vascular endothelial growth factor inhibitors. Numerous clinical trials are ongoing or completed, including phase 3 data for the mammalian target of rapamycin inhibitor everolimus in patients with HER2-resistant breast cancer. This review considers the molecular mechanisms associated with HER2 resistance and evaluates the evidence for use of evolving strategies in patients with HER2-resistant breast cancer.

A role for the fibroblast growth factor receptor in cell fate decisions in the developing vertebrate retina

Development ◽  
1998 ◽  
Vol 125 (20) ◽  
pp. 3967-3975 ◽  
Author(s):  
S. McFarlane ◽  
M.E. Zuber ◽  
C.E. Holt
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cell Fate ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Retinal Cell ◽  
Fibroblast Growth ◽  
Cell Fate Decisions ◽  
Mutant Receptor ◽  
Vertebrate Retina

The mature vertebrate retina contains seven major cell types that develop from an apparently homogenous population of precursor cells. Clonal analyses have suggested that environmental influences play a major role in specifying retinal cell identity. Fibroblast growth factor-2 is present in the developing retina and regulates the survival, proliferation and differentiation of developing retinal cells in culture. Here we have tested whether fibroblast growth factor receptor signaling biases retinal cell fate decisions in vivo. Fibroblast growth factor receptors were inhibited in retinal precursors in Xenopus embryos by expressing a dominant negative form of the receptor, XFD. Dorsal animal blastomeres that give rise to the retina were injected with cDNA expression constructs for XFD and a control non-functional mutant receptor, D48, and the cell fates of transgene-expressing cells in the mature retina determined. Fibroblast growth factor receptor blockade results in almost a 50% loss of photoreceptors and amacrine cells, and a concurrent 3.5-fold increase in Muller glia, suggesting a shift towards a Muller cell fate in the absence of a fibroblast growth factor receptor signal. Inhibition of non-fibroblast-growth-factor-mediated receptor signaling with a third mutant receptor, HAVO, alters cell fate in an opposite manner. These results suggest that it is the balance of fibroblast growth factor and non-fibroblast growth factor ligand signals that influences retinal cell genesis.

Conservation of the Notch signalling pathway in mammalian neurogenesis

Development ◽  
1997 ◽  
Vol 124 (6) ◽  
pp. 1139-1148 ◽  
Author(s):  
J.L. Pompa de la ◽  
A. Wakeham ◽  
K.M. Correia ◽  
E. Samper ◽  
S. Brown ◽  
...  
Keyword(s):  
Cell Fate ◽  
Notch Pathway ◽  
Stem Cell Differentiation ◽  
Notch Signalling ◽  
Signalling Pathway ◽  
Notch Signalling Pathway ◽  
Altered Expression ◽  
Cell Fate Decisions ◽  
Targeted Mutation ◽  
Multiple Cell

The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.

scholarly journals Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels

2008 ◽  
Vol 28 (21) ◽  
pp. 6668-6680 ◽  
Author(s):  
Albertus T. J. Wierenga ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Expression Patterns ◽  
Activity Levels ◽  
Dependent Manner ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

ABSTRACT The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34+ cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34+ cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.

Immunohistochemical study of p185 HER2 and DF3 in primary breast cancer and correlation with CA-15-3 serum tumor marker

2002 ◽  
Vol 12 (1) ◽  
pp. 74-79
Author(s):  
C Dimas ◽  
M Frangos-Plemenos ◽  
E Kouskouni ◽  
A Kondis-Pafitis
Keyword(s):  
Breast Cancer ◽  
Tumor Marker ◽  
Primary Breast Cancer ◽  
Immunohistochemical Study ◽  
Prognostic Significance ◽  
Growth Factor Receptor ◽  
Progesterone Receptors ◽  
Her2 Overexpression ◽  
Serum Tumor Marker ◽  
Degree Of Differentiation

Abstract.Dimas C, Frangos-Plemenos M, Kouskouni E, Kondis-Pafitis A. Immunohistochemical study of p185 HER2 and DF3 in primary breast cancer and correlation with CA-15-3 serum tumor marker.Human epidermal growth factor receptor 2 (p185 HER2) oncoprotein immunohistochemical expression and DF3 antigen distribution were evaluated in 129 patients with primary breast cancer. p185 HER2 overexpession was positively correlated with the degree of differentiation, metastatic disease, progesterone receptors, and cytoplasmic distribution of DF3 antigen. p185 HER2 overexpression had prognostic significance for the disease-free interval.

Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors

2003 ◽  
Vol 31 (1) ◽  
pp. 292-297 ◽  
Author(s):  
K.U. Birkenkamp ◽  
P.J. Coffer
Keyword(s):  
Transcription Factors ◽  
Cell Survival ◽  
Cell Fate ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Acute Lymphocytic Leukaemia ◽  
Cell Fate Decisions ◽  
Forkhead Transcription Factors ◽  
Forkhead Box

Recently, the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors has been identified as direct targets of phosphoinositide 3-kinase-mediated signal transduction. The AFX (acute-lymphocytic-leukaemia-1 fused gene from chromosome X), FKHR (Forkhead in rhabdomyosarcoma) and FKHR-L1 (FKHR-like 1) transcription factors are directly phosphorylated by protein kinase B, resulting in nuclear export and inhibition of transcription. This signalling pathway was first identified in the nematode worm Caenorhabditis elegans, where it has a role in regulation of the life span of the organism. Studies have shown that this evolutionarily conserved signalling module has a role in regulation of both cell-cycle progression and cell survival in higher eukaryotes. These effects are co-ordinated by FOXO-mediated induction of a variety of specific target genes that are only now beginning to be identified. Interestingly, FOXO transcription factors appear to be able to regulate transcription through both DNA-binding-dependent and -independent mechanisms. Our understanding of the regulation of FOXO activity, and defining specific transcriptional targets, may provide clues to the molecular mechanisms controlling cell fate decisions to divide, differentiate or die.

Dynamics of Notch signalling in the mouse oviduct and uterus during the oestrous cycle

2016 ◽  
Vol 28 (11) ◽  
pp. 1663 ◽  
Author(s):  
D. Murta ◽  
M. Batista ◽  
A. Trindade ◽  
E. Silva ◽  
L. Mateus ◽  
...  
Keyword(s):  
Real Time ◽  
Cell Fate ◽  
Expression Patterns ◽  
Cell Signalling ◽  
Notch Signalling ◽  
Notch Receptor ◽  
Effector Proteins ◽  
Oestrous Cycle ◽  
Cell Fate Decisions ◽  
Effector Genes

The oviduct and uterus undergo extensive cellular remodelling during the oestrous cycle, requiring finely tuned intercellular communication. Notch is an evolutionarily conserved cell signalling pathway implicated in cell fate decisions in several tissues. In the present study we evaluated the quantitative real-time polymerase chain reaction (real-time qPCR) and expression (immunohistochemistry) patterns of Notch components (Notch1–4, Delta-like 1 (Dll1), Delta-like 4 (Dll4), Jagged1–2) and effector (hairy/enhancer of split (Hes) 1–2, Hes5 and Notch-Regulated Ankyrin Repeat-Containing Protein (Nrarp)) genes in the mouse oviduct and uterus throughout the oestrous cycle. Notch genes are differentially transcribed and expressed in the mouse oviduct and uterus throughout the oestrous cycle. The correlated transcription levels of Notch components and effector genes, and the nuclear detection of Notch effector proteins, indicate that Notch signalling is active. The correlation between transcription levels of Notch genes and progesterone concentrations, and the association between expression of Notch proteins and progesterone receptor (PR) activation, indicate direct progesterone regulation of Notch signalling. The expression patterns of Notch proteins are spatially and temporally specific, resulting in unique expression combinations of Notch receptor, ligand and effector genes in the oviduct luminal epithelium, uterus luminal and glandular epithelia and uterine stroma throughout the oestrous cycle. Together, the results of the present study imply a regulatory role for Notch signalling in oviduct and uterine cellular remodelling occurring throughout the oestrous cycle.

Human Epidermal Growth Factor Receptor 2 Overexpression As a Prognostic Factor in a Large Tissue Microarray Series of Node-Negative Breast Cancers

2008 ◽  
Vol 26 (35) ◽  
pp. 5697-5704 ◽  
Author(s):  
Stephen Chia ◽  
Brian Norris ◽  
Caroline Speers ◽  
Maggie Cheang ◽  
Blake Gilks ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Prognostic Factor ◽  
Growth Factor Receptor ◽  
Her2 Overexpression ◽  
Prognostic Impact ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Node Negative ◽  
Epidermal Growth

Purpose Human epidermal growth factor receptor 2 gene (HER2) is associated with a poorer outcome in node-positive breast cancer, but the results are conflicting in node-negative disease. This study assessed the prognostic impact of HER2 overexpression/amplification in a large series of node-negative breast cancers. Patients and Methods A tissue microarray (TMA) series was constructed consisting of 4,444 invasive breast cancers diagnosed in British Columbia from 1986 to 1992. Within this series, 2,026 patients were node negative, of whom 70% did not receive adjuvant systemic therapy. The TMA series was assessed for estrogen receptor (ER) and HER2. Logistic regression modeling was used to estimate odds ratios at the 10-year follow-up. Results HER2 was positive in 10.2% of the node-negative cohort. In this cohort, an inferior outcome was seen in patients with HER2-positive tumors compared with HER2-negative tumors for 10-year relapse-free survival (RFS; 65.9% v 75.5%, respectively; P = .01), distant RFS (71.2% v 81.8%, respectively; P = .004), and breast cancer–specific survival (BCSS; 75.5% v 86.3%, respectively; P = .001). A trend for a worse overall survival was also seen (P = .06). HER2 was an independent poor prognostic factor for RFS and BCSS at 10 years, with odds ratios of 1.71 (P = .01) and 2.03 (P = .003), respectively. The number of HER2-positive tumors that were ≤ 1 cm was small, but there was a trend for a worse outcome in T1b tumors. Conclusion HER2 overexpression/amplification is correlated with a poorer outcome in node-negative breast cancer. Larger studies are needed to more clearly define the prognostic impact of HER2 in tumors ≤ 1 cm, particularly within the separate hormone receptor subgroups.

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