DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed , an atlas of cysteine ligandability compiled across 416 cancer cell lines.

Direct detection of OXA-48-like carbapenemase variants with and without co-expression of an extended-spectrum β-lactamase from bacterial cell lysates using mass spectrometry.

Introduction: Antibiotic-resistant Gram-negative bacteria are of a growing concern globally, especially those producing enzymes conferring resistance. OXA-48-like carbapenemases hydrolyze most β-lactam antibiotics, with typically low-level hydrolysis of carbapenems, but have limited effect on broad-spectrum cephalosporins. These are frequently co-expressed with extended spectrum β-lactamases, especially CTX-M-15, which typically shows high level resistance to broad-spectrum cephalosporins, yet is carbapenem susceptible.

Rapid MRSA detection via tandem mass spectrometry of the intact 80 kDa PBP2a resistance protein.

Treatment of antibiotic-resistant infections is dependent on the detection of specific bacterial genes or proteins in clinical assays. Identification of methicillin-resistant Staphylococcus aureus (MRSA) is often accomplished through the detection of penicillin-binding protein 2a (PBP2a). With greater dependence on mass spectrometry (MS)-based bacterial identification, complementary efforts to detect resistance have been hindered by the complexity of those proteins responsible.

Direct detection of intact carbapenemase variants from cell lysates: Identification, characterization and clinical implications.

Introduction: Carbapenemase-producing organisms (CPOs) are a growing threat to human health. Among the enzymes conferring antibiotic resistance produced by these organisms, carbapenemase (KPC) is considered to be a growing global health threat. Reliable and specific detection of this antibiotic resistance-causing enzyme is critical both for effective therapy and to mitigate further spread.

Epidermal growth factor receptor downregulation by small heterodimeric binding proteins.

No single engineered protein has been shown previously to robustly downregulate epidermal growth factor receptor (EGFR), a validated cancer target. A panel of fibronectin-based domains was engineered to bind with picomolar to nanomolar affinity to multiple epitopes of EGFR. Monovalent and homo- and hetero-bivalent dimers of these domains were tested for EGFR downregulation.

Transforming growth factor-β and the hallmarks of cancer.

Tumorigenesis is in many respects a process of dysregulated cellular evolution that drives malignant cells to acquire six phenotypic hallmarks of cancer, including their ability to proliferate and replicate autonomously, to resist cytostatic and apoptotic signals, and to induce tissue invasion, metastasis, and angiogenesis. Transforming growth factor-β (TGF-β) is a potent pleiotropic cytokine that functions as a formidable barrier to the development of cancer hallmarks in normal cells and tissues. Paradoxically, tumorigenesis counteracts the tumor suppressing activities of TGF-β, thus enabling TGF-β to stimulate cancer invasion and metastasis.

Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling.

Due to its common dysregulation in epithelial-based cancers and extensive characterization of its role in tumor growth, epidermal growth factor receptor (EGFR) is a highly validated target for anticancer therapies. There has been particular interest in the development of monoclonal antibodies (mAbs) targeting EGFR, resulting in two approved mAb-based drugs and several others in clinical trials. It has recently been reported that treatment with combinations of noncompetitive mAbs can induce receptor clustering, leading to synergistic receptor down-regulation.

X-linked inhibitor of apoptosis protein and its E3 ligase activity promote transforming growth factor-{beta}-mediated nuclear factor-{kappa}B activation during breast cancer progression.

The precise sequence of events that enable mammary tumorigenesis to convert transforming growth factor-beta (TGF-beta) from a tumor suppressor to a tumor promoter remains incompletely understood. We show here that X-linked inhibitor of apoptosis protein (xIAP) is essential for the ability of TGF-beta to stimulate nuclear factor-kappaB (NF-kappaB) in metastatic 4T1 breast cancer cells. Indeed whereas TGF-beta suppressed NF-kappaB activity in normal mammary epithelial cells, those engineered to overexpress xIAP demonstrated activation of NF-kappaB when stimulated with TGF-beta.

Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms.

Although it is well established that mammary tumorigenesis converts transforming growth factor-beta (TGF-beta) from a tumor suppressor to a tumor promoter, the molecular, cellular and microenvironmental mechanisms underlying the dichotomous nature of TGF-beta in mammary epithelial cells (MECs) remains to be determined definitively. Aberrant upregulation of the inducible cyclooxygenase, Cox-2, occurs frequently in breast cancers and is associated with increasing disease severity and the acquisition of metastasis; however, the impact of Cox-2 expression on normal and malignant MEC response to TGF-beta remains unknown. We show here that TGF-beta induced Cox-2 expression in normal MECs during their acquisition of an epithelial-mesenchymal transition (EMT) phenotype.

Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression.

The conversion of transforming growth factor beta (TGF-beta) from a tumor suppressor to a tumor promoter occurs frequently during mammary tumorigenesis, yet the molecular mechanisms underlying this phenomenon remain undefined. We show herein that TGF-beta repressed nuclear factor-kappaB (NF-kappaB) activity in normal NMuMG cells, but activated this transcription factor in their malignant counterparts, 4T1 cells, by inducing assembly of TGF-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1):I kappaB kinase beta (IKK beta) complexes, which led to the stimulation of a TAK1:IKK beta:p65 pathway. TAB1:IKK beta complexes could only be detected in NMuMG cells following their induction of epithelial-mesenchymal transition (EMT), which, on TGF-beta treatment, activated NF-kappaB.

Role of transforming growth factor-beta in cancer progression.

Invasion and metastasis are the most lethal characteristics of cancer and the leading causes of cancer-related death. Transforming growth factor (TGF)-beta is a multifunctional cytokine that normally functions to prevent the uncontrolled proliferation of epithelial, endothelial and hematopoietic cells. Quite dichotomously, however, aberrant genetic or epigenetic events often negate the cytostatic function of TGF-beta in these cells, leading to tumor formation.

Fibulins 3 and 5 antagonize tumor angiogenesis in vivo.

Lethal tumor growth and progression cannot occur without angiogenesis, which facilitates cancer cell proliferation, survival, and dissemination. Fibulins (FBLN) 5 and 3 are widely expressed extracellular matrix proteins that regulate cell proliferation in a context-specific manner. Reduced FBLN-5 expression has been associated with cancer formation and progression in humans, whereas its constitutive expression antagonizes endothelial cell angiogenic sprouting in vitro.

The use of cystatin C to inhibit epithelial-mesenchymal transition and morphological transformation stimulated by transforming growth factor-beta.

Introduction: Transforming growth factor-beta (TGF-beta) is a potent suppressor of mammary epithelial cell (MEC) proliferation and is thus an inhibitor of mammary tumor formation. Malignant MECs typically evolve resistance to TGF-beta-mediated growth arrest, enhancing their proliferation, invasion, and metastasis when stimulated by TGF-beta. Recent findings suggest that therapeutics designed to antagonize TGF-beta signaling may alleviate breast cancer progression, thereby improving the prognosis and treatment of breast cancer patients.

SPARC inhibits epithelial cell proliferation in part through stimulation of the transforming growth factor-beta-signaling system.

Secreted protein, acidic and rich in cysteine (SPARC) is a multifunctional secreted protein that regulates cell-cell and cell-matrix interactions, leading to alterations in cell adhesion, motility, and proliferation. Although SPARC is expressed in epithelial cells, its ability to regulate epithelial cell growth remains largely unknown. We show herein that SPARC strongly inhibited DNA synthesis in transforming growth factor (TGF)-beta-sensitive Mv1Lu cells, whereas moderately inhibiting that in TGF-beta-insensitive Mv1Lu cells (i.