Siah-1 binds and regulates the function of Numb

Mechanical forces are now recognized as key cellular effectors that together with genetic and cellular signals physically shape and pattern tissues and organs during development. Increasing efforts are aimed toward understanding the less explored role of mechanical forces in controlling cell fate decisions in embryonic development. Here we discuss recent examples of how differential forces feedback into cell fate specification and tissue patterning. In particular, we focus on the role of actomyosin-contractile force generation and transduction in affecting tissue morphogenesis and cell fate regulation in the embryo.

Although the stem cells of various tissues remain in the quiescent state to maintain their undifferentiated state, they also undergo cell divisions as required, and if necessary, even a single stem cell is able to provide for lifelong tissue homeostasis. Stem cell populations are precisely controlled by the balance between their symmetric and asymmetric divisions, with their division patterns determined by whether the daughter cells involved retain their self-renewal capacities. Recent studies have reported that metabolic pathways and the distribution of mitochondria are regulators of the division balance of stem cells and that metabolic defects can shift division balance toward symmetric commitment, which leads to stem cell exhaustion. It has also been observed that in asymmetric division, old mitochondria, which are central metabolic organelles, are segregated to the daughter cell fated to cell differentiation, whereas in symmetric division, young and old mitochondria are equally distributed between both daughter cells. Thus, metabolism and mitochondrial biology play important roles in stem cell fate decisions. As these decisions directly affect tissue homeostasis, understanding their regulatory mechanisms in the context of cellular metabolism is critical.

Transcriptional networks regulate cell fate decisions, which occur at the level of individual cells. However, much of what we know about their structure and function comes from studies averaging measurements over large populations of cells, many of which are functionally heterogeneous. Such studies conceal the variability between cells and so prevent us from determining the nature of heterogeneity at the molecular level. In recent years, many protocols and platforms have been developed that allow the high throughput analysis of gene expression in single cells, opening the door to a new era of biology. Here, we discuss the need for single cell gene expression analysis to gain deeper insights into the transcriptional control of cell fate decisions, and consider the insights it has provided so far into transcriptional regulatory networks in development.

In tumors, cancer cells are frequently exposed to adverse environmental conditions that result in endoplasmic reticulum (ER) stress. Mechanical signals emerging from extracellular matrix (ECM) rigidity and cell shape regulate the activity of transcriptional co-activators Yes-associated protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding motif (TAZ). However, the role of ECM rigidity and YAP/TAZ in tumor cell fate decisions under ER stress remains relatively unexplored. Our results suggest that the YAP/TAZ system plays an important role in the control of ER stress-induced cell death by mechanical signaling arising from ECM stiffness in tumor cells. Mechanistically, YAP/TAZ regulates apoptosis induced by ER stress in tumor cells by controlling the activation of the TRAIL-R2/DR5-mediated extrinsic apoptotic pathway through a dual mechanism. On the one hand, the YAP/TAZ system prevents intracellular TRAIL-R2/DR5 clustering in tumor cells. On the other hand, it inhibits cFLIP down-regulation in tumor cells experiencing ER stress. In addition, YAP/TAZ controls the expression of pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells undergoing ER stress by a TRAIL-R2/DR5/caspase-8-dependent mechanism. Although other mechanisms may also be involved in controlling cell death and inflammation in tumor cells facing environmental stress, our results support a model in which regulation of the subcellular localization and activity of the YAP/TAZ transcriptional co-activators could contribute to the microenvironmental control of cell fate decisions in tumor cells undergoing ER stress.

The endothelium is attracting increasing attention from oncologists and cardiologists. Inhibition of angiogenesis in tumours by the induction of endothelial injury is considered a promising therapeutic approach. Conversely, endothelial injury is implicated in atherosclerosis, thrombosis, hypertension, and diabetes. Endothelial death occurs by apoptosis and the regenerative capacity of mature endothelial cells is limited: wherever an imbalance between death and regeneration of the endothelium occurs, its integrity and function is threatened and the origin and progression of cardiovascular disease is favoured. Notch signalling is involved in the cell fate decision and, directly or by cross-talking with other pathways, has been shown to regulate apoptosis, regeneration, proliferation, and migration of endothelial cells.1,2 Inhibition of the Notch pathways is useful in oncology to repress angiogenesis in tumours3,4 but its manipulation could be useful in cardiology to reduce endothelial apoptosis and to favour angiogenesis. The leitmotiv of this short review is a cross-talk between a cell biologist, an oncologist, and a cardiologist with the goal to examine data relevant to the role of the Notch system on the endothelium. It is a highly conserved pathway from invertebrates to mammals5 that controls cell fate decisions. It is a short range communication system between two adjacent cells based on a ligand-activated receptor. Mammals express four highly homologous receptors (Notch 1, 2, 3, and 4) and five canonical ligands (Delta-like 1,3, 4 and Jagged 1, 2). Both receptors and ligands are membrane-spanning proteins ( Figure 1 ). Ligand binding separates the extracellular domain of Notch from the transmembrane domain allowing the first proteolytic cut by a surface protease, ADAM10 (A Disintegrin And Metalloprotease), which removes the extracellular portion of Notch and creates a membrane-tethered intermediate that is a substrate for γ-secretase, an intramembranous aspartylprotease complex. γ-Secretase in turn generates the active form …

We have recently gained an unprecedented knowledge of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC). We have also learned that the aberrant function of multiple signaling networks contributes to HNSCC initiation and progression, including the persistent activation of the PI3K/Akt/mTOR, NFκB, and STAT3 signaling pathways and decreased antiproliferative responses to Notch and TGF-β. Emerging evidence suggests that many regulatory components of the Wnt signaling pathway are also dysfunctional in HNSCC, leading to increased nuclear β-catenin levels. This includes increased expression of Wnt family members and their coreceptor, Frizzled, loss of heterozygosity of the adenomatosis polyposis coli (APC) tumor suppressor gene, and epigenetic events leading to decreased expression of APC and the Wnt antagonists the secreted Frizzled-related proteins (SFRPs), Wnt inhibitory factors (WIFs) and Dickkopf family members (DKKs), primarily by promoter hypermethylation. Wnt/β-catenin controls cell fate decisions in normal epithelial stem cells, but persistent β-catenin signaling contributes to increased growth, metastatic potential and resistance to chemotherapy in HNSCC and their tumor-initiating cells. While the role of Wnt/β-catenin in HNSCC is not as well defined as in other cancers, the development of small molecule inhibitors of the Wnt/β-catenin pathway for other cancer types may soon afford novel targeted options for the treatment of HNSCC lesions displaying aberrant Wnt signaling.

Cross-species stromal signaling programs human embryonic stem cell differentiation

MYC and MYCN have been directly implicated in the transcriptional regulation of several thousand genes in pluripotent stem cells and possibly contribute to the activity of all transcribed genes. Control of transcription by a pause-release mechanism, recruitment of positive and negative epigenetic regulators, and a general role in transcriptional amplification have all been implicated as part of the broad, overarching mechanism by which MYC controls stem cell biology. As would be anticipated from the regulation of so many genes, MYC is involved in a wide range of cellular processes including cell-cycle control, metabolism, signal transduction, self-renewal, maintenance of pluripotency, and control of cell fate decisions. MYC transcription factors also have clear roles in cell reprogramming and establishment of the pluripotent state. The mechanism by which MYC accomplishes this is now being explored and promises to uncover unexpected facets of general MYC regulation that are likely to be applicable to cancer biology. In this work we review our current understanding of how MYC contributes to the maintenance and establishment of pluripotent cells and how it contributes to early embryonic development.

Bistable regulatory elements enhance heterogeneity in cell populations and, in multicellular organisms, allow cells to specialize and specify their fate. Our study demonstrates that in a system of bistable genetic switch, the noise characteristics control in which of the two epigenetic attractors the cell population will settle. We focus on two types of noise: the gene switching noise and protein dimerization noise. We found that the change of magnitudes of these noise components for one of the two competing genes introduces a large asymmetry of the protein stationary probability distribution and changes the relative probability of individual gene activation. Interestingly, an increase of noise associated with a given gene can either promote or suppress the activation of the gene, depending on the type of noise. Namely, each gene is repressed by an increase of its gene switching noise and activated by an increase of its protein-product dimerization noise. The observed effect was found robust to the large, up to fivefold deviations of the model parameters. In summary, we demonstrated that noise itself may determine the relative strength of the epigenetic attractors, which may provide a unique mode of control of cell fate decisions.

Ectodysplasin receptor Edar and its ligand Eda A1, as well as their related receptor Xedar and ligand Eda A2, are recently discovered members of the tumor necrosis factor superfamily that signal predominantly through the nuclear factor-kappaB and c-jun N-terminal kinases pathways. Mutations in genes that encode proteins involved in Edar signaling pathway cause hypohidrotic ectodermal displasias in humans and mice and characterized by severe defects in development of ectodermal appendages including hairs, teeth, and exocrine glands. Here, we summarize the current knowledge of molecular mechanisms underlying the involvement of Edar signaling pathway in controlling hair follicle (HF) development and cycling. Genetic and experimental studies suggest that Edar signaling is involved in the control of cell fate decision in embryonic epidermis, as well as in the regulation of cell differentiation programs in the HF. Loss or gain of Edar signaling affects the initiation of several HF types (guard and zig-zag HF), hair shaft formation, as well as sebaceous gland morphology. We also review data on the cross-talk between Edar and Wnt, transforming growth factor-beta/bone morphogenic protein/activin, and Shh signaling pathways in the control of HF development and cycling.

The vertebrate endocrine pancreas has the crucial function of maintaining blood sugar homeostasis. This role is dependent upon the development and maintenance of pancreatic islets comprising appropriate ratios of hormone-producing cells. In all vertebrate models studied, an initial precursor population of Pdx1-expressing endoderm cells gives rise to separate endocrine and exocrine cell lineages. Within the endocrine progenitor pool a variety of transcription factors influence cell fate decisions, such that hormone-producing differentiated cell types ultimately arise, including the insulin-producing beta cells and the antagonistically acting glucagon-producing alpha cells. In previous work, we established that the development of all pancreatic lineages requires retinoic acid (RA) signaling. We have used the zebrafish to uncover genes that function downstream of RA signaling, and here we identify mnx1 (hb9) as an RA-regulated endoderm transcription factor-encoding gene. By combining manipulation of gene function, cell transplantation approaches and transgenic reporter analysis we establish that Mnx1 functions downstream of RA within the endoderm to control cell fate decisions in the endocrine pancreas progenitor lineage. We confirm that Mnx1-deficient zebrafish lack beta cells, and, importantly, we make the novel observation that they concomitantly gain alpha cells. In Mnx1-deficient embryos, precursor cells that are normally destined to differentiate as beta cells instead take on an alpha cell fate. Our findings suggest that Mnx1 functions to promote beta and suppress alpha cell fates.

T lymphocytes consist of several subtypes with distinct functions that help to coordinate an immune response. They are generated within the thymus through a sequential developmental pathway that produces subsets with diverse antigen specificities and functions. Naïve T cells populate peripheral lymphoid organs and are activated upon foreign antigen encounter. While most T cells die soon after activation, a memory population survives and is able to quickly respond to secondary challenges, thus providing long-term immunity to the host. Although cell identity is largely stable and is instructed by cell-specific transcriptional programs, cells may change their transcriptional profiles to be able to adapt to new functionalities. Central to these dynamic processes are transcription factors, which control cell fate decisions, through direct regulation of gene expression. In this book chapter, we review the functions of the transcription factor B-cell lymphoma 6 (BCL6), which directs the fate of several lymphocyte subsets, including helper, cytotoxic, and innate-like T cells, but can also be involved in lymphomagenesis in humans.

Chromatin regulation and dynamics in stem cells.

The transcription factor p53 is the core of the cellular stress network, which controls cell fate decisions on genotoxic stress in a dynamics response manner. Mdm2 is an E3 ubiquitin ligase, which play a dual role in p53 regulation, that is, on the one hand, Mdm2 destroys the stability of p53 via ubiquitin labeling, and on the other hand, Mdm2 increase the efficiency of p53 production through binding p53 messenger RNA. A number of models indicate that Mdm2's inhibitory function on p53 plays a constructive role in the p53-Mdm2 vibrator, the research of how Mdm2's promotion function on p53 regulates the dynamics of this gene network, however, is still lacking. To this end, this paper uses a mathematical model to comprehensively explore the influence of the Mdm2 up-regulation p53 pathway on p53 dynamics. We adopt the ordinary differential equations (ODE) model and the bifurcation analysis method to investigate the multiple role of Mdm2 on p53 gene networks dynamics control. The results show that the phosphorylation of Mdm2 at Ser395, which forming a positive feedback loop (PFL) with p53, is essential for the oscillation of this gene network and may be the reason why there is a bimodal switch of p53 kinetics under etoposide stimulation; the previously reported phosphatase Wip1 is required for the oscillation of p53, which may only occur in situations where the intensity of the PFL mediated by phosphorylated Mdm2 is high, and we predict that Wip1 will inhibit the p53 oscillation in some weak PFL cases; Finally, our model also proves that Mdm2 promotes the deactivation and ubiquitination degradation of p53 is a key factor in the occurrence of repeated vibration dynamics of p53. The main conclusions of this paper are exhibited in some two-dimensional bifurcation diagrams. In order to confirm these bifurcation phenomena, we discuss the case where the Hill coefficient describing the degree of nonlinearity is small. As a result, there is no obvious shape change of the bifurcation curves surrounding the oscillation region. The robustness of these conclusions is verified again. We believe that our results can play a guiding role in the future related experiments of p53 kinetics.

e13537 Background: Increased protein expression of CREB, a DNA damage-regulated transcription factor, has been associated with poor survival in advanced NSCLC. We have demonstrated that exposure of cancer cell lines to low dose ionizing radiation (IR) increased pCREB on a Ser133 residue. However, exposure to high dose IR correlated with pCREB on Ser121 by ATM, a master regulator of the cellular DNA damage response. This unusual bimodal response of CREB to IR, reflected by activation at low doses and attenuation at high doses, suggested that CREB may control cell fate decisions in response to DNA damage. We hypothesized that patterns of protein expression of CREB, pCREB Ser133, and ATM would predict treatment response in pts who have undergone radiotherapy for locally advanced NSCLC. Methods: Diagnostic tumor specimens were obtained from pts who underwent thoracic radiation in a clinical trial for locally advanced NSCLC. Protein expression of CREB, pCREB Ser133, and ATM was assessed by AQUA. Wilcoxon rank sum test was used to assess differences in protein expression. Univariate regression was conducted to evaluate protein expression and clinical outcomes. Kruskal Wallis test was used to assess protein expression and pneumonitis. Results: Sufficient tumor tissue was available for 35 of 79 pts enrolled. Best responses in 6 months included 12% CR, 73% PR, 9% SD, and 6% PD. Pre-treatment protein expression per AQUA analyses of CREB, pCREB Ser133, and ATM were not statistically associated with time to in-field progression, time to out-of-field progression, time to distant metastasis, best response, pneumonitis, or overall survival. Unexpectedly, increased expression of pCREB Ser133 was associated with durable anti-tumor response to radiation at a median duration of 14.6 months (p=0.03). Conclusions: Protein expression per AQUA of CREB, pCREB Ser133, and ATM did not confirm our hypotheses, possibly related to our limited sample size. Further analysis of the role of CREB in response to IR in cancer pts is ongoing.