Stat5 Exerts Distinct, Vital Functions in the Cytoplasm and Nucleus of Bcr-Abl+ K562 and Jak2(V617F)+ HEL Leukemia Cells.

Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns.

The inhibition of stat5 by a Peptide aptamer ligand specific for the DNA binding domain prevents target gene transactivation and the growth of breast and prostate tumor cells.

The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines.

Inhibition of Stat3 by peptide aptamer rS3-PA enhances growth suppressive effects of irinotecan on colorectal cancer cells.

Abstract Cytotoxic agents, alone or in combination, are being used in the treatment of colorectal cancer. Despite progress in the therapeutic regimes, this common malignancy is still the cause of considerable morbidity and mortality, and further improvements are required. Cancer cells often exhibit intrinsic resistance against chemotherapeutic agents or they develop resistance over the time of treatment.

Stat3 is activated in skin lesions by the local application of imiquimod, a ligand of TLR7, and inhibited by the recombinant peptide aptamer rS3-PA.

Abstract Signal transducer and activator of transcription 3 (Stat3) assumes central functions in the regulation of apoptosis, proliferation, angiogenesis, and immune responses in normal cells. It also plays crucial roles in inflammatory and malignant diseases and in the cellular communication in the tissue microenvironment. Signaling interactions among normal endothelial cells, immune cells, and tumor cells, mediated by the release of cytokines, chemokines, and growth factors, often result in the activation of Stat3 and promotion of cancer cell proliferation, invasion, angiogenesis, and immune evasion.

Survivin inhibition by an interacting recombinant peptide, derived from the human ferritin heavy chain, impedes tumor cell growth.

Background: Proteins involved in the aberrant regulation of signaling pathways and their downstream effectors are promising targets for cancer therapy. Survivin is an anti-apoptotic and cell cycle-promoting protein, which is consistently overexpressed in cancer cells. In normal cells, its expression is tightly controlled by signaling pathways and their associated transcriptional activators and repressors.

A membrane penetrating peptide aptamer inhibits STAT3 function and suppresses the growth of STAT3 addicted tumor cells.

Cancer cells are characterized by the aberrant activation of signaling pathways governing proliferation, survival, angiogenesis, migration and immune evasion. These processes are partially regulated by the transcription factor STAT3. This factor is inappropriately activated in diverse tumor types.

The integration of a Stat3 specific peptide aptamer into the thioredoxin scaffold protein strongly enhances its inhibitory potency.

We are characterizing peptides which are able to interact with functional domains of oncoproteins and thus inhibit their activity. The yeast two-hybrid system was used to derive a peptide sequence which specifically interacts with the dimerization domain of the transcription factor Stat3. The activated form of Stat3 is required for the survival of many transformed cells and Stat3 inhibition can cause tumor cell death.

The intracellular delivery of a recombinant peptide derived from the acidic domain of PIAS3 inhibits STAT3 transactivation and induces tumor cell death.

Signaling components, which confer an "addiction" phenotype on cancer cells, represent promising drug targets. The transcription factor signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many different types of tumor cells and its activity is indispensible in a large fraction. We found that the expression of the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3 (PIAS3), positively correlates with STAT3 activation in normal cells.

Visualization of Stat3 and Stat5 transactivation activity with specific response element dependent reporter constructs integrated into lentiviral gene transfer vectors.

Background: Signal transducer and activator of transcription 3 and 5 (Stat3 and Stat5) play important roles in cell differentiation, proliferation, apoptosis and inflammation. They are transiently activated by ligand-receptor interactions in normal cells but are often found to be constitutively active in cancer cells. Analysis of their activation pattern is therefore important for the description of developmental processes and the understanding of cellular transformation.

The function of Stat3 in tumor cells and their microenvironment.

Stat3 was initially recognized as a transcription factor and mediates the nuclear action of many different cytokines and growth factors. In addition to its roles in normal cell function, the inappropriate activation of Stat3 in tumor cells has attracted the attention of tumor biologists and has led to the consideration of Stat3 as a drug target. The induction of Stat3 activity under physiological circumstances is transient and many different levels of activation and deactivation have been defined.

Peptide aptamer libraries.

Peptide aptamers are molecules that bind to protein targets and are able to interfere with their functions. In the past, important achievements have been made using such peptide aptamers in different approaches and for various purposes. Peptide aptamers are comprised of a variable peptide region of 8 to 20 amino acids in length, which is displayed by a scaffold protein.

Monomeric recombinant peptide aptamers are required for efficient intracellular uptake and target inhibition.

Signal transduction events often involve the assembly of protein complexes dependent on modular interactions. The inappropriate assembly of modular components plays a role in oncogenic transformation and can be exploited for therapeutic purposes. Selected peptides embedded in the context of a scaffold protein can serve as competitive inhibitors of intracellular protein functions in cancer cells.

Peptide aptamers with binding specificity for the intracellular domain of the ErbB2 receptor interfere with AKT signaling and sensitize breast cancer cells to Taxol.

The ErbB2 receptor tyrosine kinase is overexpressed in approximately 30% of breast tumor cases and its overexpression correlates with an unfavorable prognosis. A major contributor for this course of the disease is the insensitivity of these tumors toward chemotherapy. Monoclonal antibodies, inhibiting the ligand-induced activation of the receptor and tyrosine kinase inhibitors acting on the intrinsic enzymatic activity of the intracellular domain, have been developed as targeted drugs.

The biological functions of the versatile transcription factors STAT3 and STAT5 and new strategies for their targeted inhibition.

Signal transducers and activators of transcription (STATs) comprise a unique family of transcription factors, which transmit the interactions of cytokines, hormones and growth factors with their cell surface receptors into transcriptional programs. The mechanism of STAT activation has been well-established and comprises tyrosine phosphorylation, dimerization, nuclear translocation, binding to specific DNA response elements, recruitment of co-activators or co-repressors and transcriptional induction or repression of target genes. Gene deletion, microarrays, proteomics and chromatin immunoprecipitation experiments have revealed target genes with a broad range of functions regulated by STAT3 and STAT5.

Current strategies for the development of peptide-based anti-cancer therapeutics.

The completion of the human genome sequence and the development of new techniques, which allow the visualisation of comprehensive gene expression patterns, has led to the identification of a large number of gene products differentially expressed in tumours and corresponding normal tissues. The task at hand is the sorting of these genes into correlative and causative ones. Correlative genes are merely changed as a consequence of transformation and have no decisive effects upon transformation.

Peptide aptamers: recent developments for cancer therapy.

During the past two decades, our understanding of oncogenesis has advanced considerably and many new signalling pathways have been identified. Differences in signalling events that distinguish normal cells from tumour cells provide new targets for the development of anticancer agents. Peptide aptamers are small peptide sequences that have been selected to recognise a predetermined target protein domain and are potentially able to interfere with its function.

Rtg2 protein links metabolism and genome stability in yeast longevity.

Mitochondrial dysfunction induces a signaling pathway, which culminates in changes in the expression of many nuclear genes. This retrograde response, as it is called, extends yeast replicative life span. It also results in a marked increase in the cellular content of extrachromosomal ribosomal DNA circles (ERCs), which can cause the demise of the cell.

A mutation in the ATP2 gene abrogates the age asymmetry between mother and daughter cells of the yeast Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae reproduces by asymmetric cell division, or budding. In each cell division, the daughter cell is usually smaller and younger than the mother cell, as defined by the number of divisions it can potentially complete before it dies. Although individual yeast cells have a limited life span, this age asymmetry between mother and daughter ensures that the yeast strain remains immortal.

Copper homeostasis and aging in the fungal model system Podospora anserina: differential expression of PaCtr3 encoding a copper transporter.

Lifespan extension of Podospora anserina mutant grisea is caused by a loss-of-function mutation in the nuclear gene Grisea. This gene encodes the copper regulated transcription factor GRISEA recently shown to be involved in the expression of PaSod2 encoding the mitochondrial manganese superoxide dismutase. Here we report the identification and characterization of a second target gene.

Respiration, copper availability and SOD activity in P. anserina strains with different lifespan.

P. anserina mutants with impairments in complex IV (COX) of the respiratory chain are characterized by an increase in lifespan. Examples are the nuclear grisea mutant with a moderate lifespan extension (60%) and the immortal extranuclear ex1 mutant.