In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis.

In mouse and human neural progenitor and glioblastoma "stem-like" cells, we identified key targets of the Polycomb-group protein BMI1 by combining ChIP-seq with in vivo RNAi screening. We discovered that Bmi1 is important in the cellular response to the transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) and endoplasmic reticulum (ER) stress pathways, in part converging on the Atf3 transcriptional repressor. We show that Atf3 is a tumor-suppressor gene inactivated in human glioblastoma multiforme together with Cbx7 and a few other candidates.

Snail and Slug, key regulators of TGF-β-induced EMT, are sufficient for the induction of single-cell invasion.

TGF-β plays a dual role in cancer; in early stages it inhibits tumor growth, whereas later it promotes invasion and metastasis. TGF-β is thought to be pro-invasive by inducing epithelial-to-mesenchymal transition (EMT) via induction of transcriptional repressors, including Slug and Snail. In this study, we investigated the role of Snail and Slug in TGF-β-induced invasion in an in vitro invasion assay and in an embryonic zebrafish xenograft model.

UBE2O negatively regulates TRAF6-mediated NF-κB activation by inhibiting TRAF6 polyubiquitination.

Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is a key regulator of the activation of transcription factor NF-κB by the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily. Recruitment of TRAF6 to the receptor-associated IRAK1-IRAK4-MyD88 adaptor protein complex induces lysine 63 (K63) autopolyubiquitination of TRAF6, which leads to further recruitment of downstream regulators, such as TAB2/3 and TAK1, and subsequently triggers NF-κB activation. Here, we identified the putative E2 ubiquitin-conjugating (UBC) enzyme UBE2O as a novel negative regulator of TRAF6-dependent NF-κB signaling.

The cancer secretome, current status and opportunities in the lung, breast and colorectal cancer context.

Despite major improvements on the knowledge and clinical management, cancer is still a deadly disease. Novel biomarkers for better cancer detection, diagnosis and treatment prediction are urgently needed. Proteins secreted, shed or leaking from the cancer cell, collectively termed the cancer secretome, are promising biomarkers since they might be detectable in blood or other biofluids.

Endoglin for tumor imaging and targeted cancer therapy.

Introduction: Although cancer treatment has evolved substantially in the past decades, cancer-related mortality rates are still increasing. Therapies targeting tumor angiogenesis, crucial for the growth of solid tumors, mainly target vascular endothelial growth factor (VEGF) and have been clinically applied during the last decade. However, these therapies have not met high expectations, which were based on therapeutic efficacy in animal models.

Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts.

The interaction between epithelial cancer cells and cancer-associated fibroblasts (CAFs) has a major role in cancer progression and eventually in metastasis. In colorectal cancer (CRC), CAFs are present in high abundance, but their origin and functional interaction with epithelial tumor cells has not been elucidated. In this study we observed strong activation of the transforming growth factor-β (TGF-β)/Smad signaling pathway in CRC CAFs, accompanied by decreased signaling in epithelial tumor cells.

The prognostic role of TGF-β signaling pathway in breast cancer patients.

Background: The transforming growth factor-β (TGF-β) pathway has dual effects on tumor growth. Seemingly, discordant results have been published on the relation between TGF-β signaling markers and prognosis in breast cancer. Improved prognostic information for breast cancer patients might be obtained by assessing interactions among TGF-β signaling biomarkers.

Soluble fms-like tyrosine kinase 1 and soluble endoglin are elevated circulating anti-angiogenic factors in pre-eclampsia.

Pre-eclampsia, characterized by hypertension and proteinuria, affects approximately 3-5% of all pregnancies worldwide and is a major cause of maternal and fetal morbidity and mortality. Maternal endothelial dysfunction is associated with disease pathogenesis. Recently, reports have shown that elevated levels of circulating soluble fms-like tyrosine kinase 1 [sFlt1] and soluble endoglin [sEng] are associated with pre-eclampsia.

Overactive bone morphogenetic protein signaling in heterotopic ossification and Duchenne muscular dystrophy.

Bone morphogenetic proteins (BMPs) are important extracellular cytokines that play critical roles in embryogenesis and tissue homeostasis. BMPs signal via transmembrane type I and type II serine/threonine kinase receptors and intracellular Smad effector proteins. BMP signaling is precisely regulated and perturbation of BMP signaling is connected to multiple diseases, including musculoskeletal diseases.

Fas-associated factor 1 is a scaffold protein that promotes β-transducin repeat-containing protein (β-TrCP)-mediated β-catenin ubiquitination and degradation.

FAS-associated factor 1 (FAF1) antagonizes Wnt signaling by stimulating β-catenin degradation. However, the molecular mechanism underlying this effect is unknown. Here, we demonstrate that the E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP) is required for FAF1 to suppress Wnt signaling and that FAF1 specifically associates with the SCF (Skp1-Cul1-F-box protein)-β-TrCP complex.

TGF-β signalling and its role in cancer progression and metastasis.

The transforming growth factor-β (TGF-β) system signals via protein kinase receptors and SMAD mediators to regulate a large number of biological processes. Alterations of the TGF-β signalling pathway are implicated in human cancer. Prior to tumour initiation and early during progression, TGF-β acts as a tumour suppressor; however, at later stages, it is often a tumour promoter.

BMP signaling in vascular diseases.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) family that signal via type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. BMPs are multifunctional regulators of development and tissue homeostasis and they were initially characterized as inducers of bone regeneration. Genetic studies in humans and mice showed that perturbations in BMP signaling lead to various diseases, such as skeletal diseases, vascular diseases and cancer.

Role of endoglin in fibrosis and scleroderma.

Fibrosis plays a role in many pathological conditions, among which is the autoimmune disease systemic sclerosis (SSc). SSc is characterized by fibrosis in the skin and internal organs, but the etiology remains to be elucidated. Transforming growth factor-β (TGF-β) is a key player in the fibrotic process, also in SSc.

RNF12 controls embryonic stem cell fate and morphogenesis in zebrafish embryos by targeting Smad7 for degradation.

TGF-β members are of key importance during embryogenesis and tissue homeostasis. Smad7 is a potent antagonist of TGF-β family/Smad-mediated responses, but the regulation of Smad7 activity is not well understood. We identified the RING domain-containing E3 ligase RNF12 as a critical component of TGF-β signaling.

Bisindoylmaleimide I enhances osteogenic differentiation.

The Wnt/β-catenin and bone morphogenetic proteins (BMPs) pathways play important roles in controlling osteogenesis. Using a cell-based kinase inhibitor screening assay, we identified the compound bisindoylmaleimide I (BIM) as a potent agonist of the cytosolic β-catenin accumulation in preosteoblast cells. Through suppressing glycogen synthase kinase 3β enzyme activities, BIM upregulated β-catenin responsive transcription and extended duration of BMP initiated signal.

Transcription-independent function of Polycomb group protein PSC in cell cycle control.

Polycomb group (PcG) proteins control development and cell proliferation through chromatin-mediated transcriptional repression. We describe a transcription-independent function for PcG protein Posterior sex combs (PSC) in regulating the destruction of cyclin B (CYC-B). A substantial portion of PSC was found outside canonical PcG complexes, instead associated with CYC-B and the anaphase-promoting complex (APC).

Key role for ubiquitin protein modification in TGFβ signal transduction.

The transforming growth factor β (TGFβ) superfamily of signal transduction molecules plays crucial roles in the regulation of cell behavior. TGFβ regulates gene transcription through Smad proteins and signals via non-Smad pathways. The TGFβ pathway is strictly regulated, and perturbations lead to tumorigenesis.

Wnt/β-catenin signaling changes C2C12 myoblast proliferation and differentiation by inducing Id3 expression.

Canonical Wnt signaling plays important roles in regulating cell proliferation and differentiation. In this study, we report that inhibitor of differentiation (Id)3 is a Wnt-inducible gene in mouse C2C12 myoblasts. Wnt3a induced Id3 expression in a β-catenin-dependent manner.

BMP-7 inhibits TGF-β-induced invasion of breast cancer cells through inhibition of integrin β(3) expression.

Background: The transforming growth factor (TGF)-β superfamily comprises cytokines such as TGF-β and Bone Morphogenetic Proteins (BMPs), which have a critical role in a multitude of biological processes. In breast cancer, high levels of TGF-β are associated with poor outcome, whereas inhibition of TGF-β-signaling reduces metastasis. In contrast, BMP-7 inhibits bone metastasis of breast cancer cells.

Regulation of endothelial cell plasticity by TGF-β.

Recent evidence has demonstrated that endothelial cells can have a remarkable plasticity. By a process called Endothelial-to-Mesenchymal Transition (EndMT) endothelial cells convert to a more mesenchymal cell type that can give rise to cells such as fibroblasts, but also bone cells. EndMT is essential during embryonic development and tissue regeneration.

GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb.

Glycogen synthase kinase 3β (GSK3β) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3β kinase activity has been reported to be critical for various types of cancer cells, but the mechanism has remained elusive. In this study we examine the mechanism by which GSK3β regulates the survival of leukemia cells.

Controlling angiogenesis by two unique TGF-β type I receptor signaling pathways.

Genetic studies in mice and humans have revealed a pivotal function for transforming growth factor-beta (TGF-β) in vascular development and maintenance of vascular homeostasis. Mice deficient for various TGF-β signaling components develop an embryonic lethality due to vascular defects. In patients, mutations in TGF-β receptors have been linked to vascular dysplasia like Hereditary Hemorrhagic Telangiectasia (HHT) and pulmonary arterial hypertension (PAH).

Exploring anti-TGF-β therapies in cancer and fibrosis.

Transforming growth factor-β (TGF-β) is a multifunctional cytokine, with important roles in maintaining tissue homeostasis. TGF-β signals via transmembrane serine/threonine kinase receptors and intracellular Smad transcriptional regulators. Perturbed TGF-β signaling has been implicated in a large variety of pathological conditions.

Elevated transforming growth factor β and mitogen-activated protein kinase pathways mediate fibrotic traits of Dupuytren's disease fibroblasts.

Background: Dupuytren's disease is a fibroproliferative disorder of the palmar fascia. The treatment used to date has mostly been surgery, but there is a high recurrence rate. Transforming growth factor β (TGF-β) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in Dupuytren's disease.

TGF-β receptor signaling pathways in angiogenesis; emerging targets for anti-angiogenesis therapy.

Angiogenesis, the formation of new blood vessels is essential for diverse physiological processes such as development, but also for pathological conditions like tumor growth. Most studied in this context are tyrosine kinase signaling pathways such as those involving vascular endothelial growth factor (VEGF). There is however accumulating evidence that more pathways are as essential for angiogenesis.