Biomedical subjects

Bernd Groner

Publications and source records attributed to Bernd Groner.

23 records · Page 2Linked to original sources

PubMed2003

Crosstalk between the extracellular domain of the ErbB2 receptor and IGF-1 receptor signaling.

Insulin-like growth factor 1 receptor (IGF-1R) plays an important role in cell growth and malignant transformation. To investigate IGF-1R-dependent signaling events and its effects on apoptosis induction and cellular proliferation, we generated a constitutively active, ligand-independent IGF-1R variant. We fused the cytoplasmic domain of the IGF-1R to the extracellular and transmembrane domains of the oncogenic ErbB2 receptor (ErbB2(V-->E)/IGF-1). A fusion protein in which the wild-type sequence of the ErbB2 receptor was used, served as a control (ErbB2(V)/IGF-1R). ErbB2(V)/IGF-1R, ErbB2(V-->E)/IGF-1R and IGF-1R were stably transfected into interleukin 3 (IL-3)-dependent BaF/3 cells. ErbB2(V-->E)/IGF-1R expressing cells exhibited ligand-independent, constitutive tyrosine phosphorylation of the receptor fusion protein. Constitutively, activated ErbB2(V-->E)/IGF-1R conferred IL-3 independence for growth and survival to the transfected BaF/3 cells. Constitutive activation of the IGF-1R results in cellular growth and protection against apoptosis upon IL-3 withdrawal in BaF/3 cells.

Animals↗

PubMed2003

Regression of cutaneous tumor lesions in patients intratumorally injected with a recombinant single-chain antibody-toxin targeted to ErbB2/HER2.

ScFv(FRP5)-ETA is a recombinant single-chain antibody-toxin with binding specificity for ErbB2/HER2. Previously potent antitumoral activity of the molecule against ErbB2 overexpressing tumor cells was demonstrated in vitro and in animal models. Here we report on the first application of scFv(FRP5)-ETA in human cancer patients summarizing case reports collected in four different clinical centers. Eleven patients suffering from metastatic breast and colorectal cancers and from malignant melanoma were treated on a compassionate-use basis by intratumoral injection of scFv(FRP5)-ETA into cutaneous lesions once daily for 7-10 days. Total daily doses ranged from 60 to 900 microg, and total doses per treatment cycle ranged from 0.6 to 6.0 mg. Treatment caused injected tumors to shrink in six of the 10 cases evaluated (60%). Complete regression of injected tumor nodules was accomplished in four patients (40%) and partial reduction in tumor size in another two patients (20%). Adverse reactions were restricted to local symptoms such as pain and inflammation at injection sites which were fully reversible. Only in one patient treated at the highest daily doses systemic liver toxicity of grade 2 was observed and treatment was discontinued on day 7. No hematologic, renal, and/or cardiovascular toxicities were noted. Our results demonstrate that local therapy with scFv(FRP5)-ETA can be effective against ErbB2 expressing tumors justifying further clinical development of this reagent.

Adult↗

PubMed2002

The Stat5-RARalpha fusion protein represses transcription and differentiation through interaction with a corepressor complex.

The transcription factor Stat5 mediates the cellular response to activation of multiple cytokine receptors involved in the regulation of proliferation and differentiation of hematopoietic cells. Recently, the human Stat5 gene was found to be translocated to the RARalpha gene in a patient with acute promyelocytic leukemia indicating that Stat5 might also play a role in cellular transformation. We investigated the mechanism by which Stat5 might exert this function and studied the biochemical and cellular functions of fusion proteins comprising Stat5 and RARalpha. The expression of Stat5-RARalpha causes the transcriptional repression of gene transcription, a process that requires the coiled-coil domain of Stat5 (amino acid positions 133-333). Oligomerization of this domain in the Stat5-RARalpha fusion protein leads to stable binding of the corepressor SMRT independent of all-trans retinoic acid (ATRA) stimulation and is accompanied by an impaired response to differentiation signals in hematopoietic cells. This inhibitory effect on myeloid differentiation cannot be overcome by simultaneous coexpression of RARalpha. We conclude that Stat5 is capable of interacting with a corepressor complex that alters the pattern of corepressor binding to RARalpha and its dissociation in response to ATRA stimulation, leading to enhanced repressor activity and a block of hematopoietic differentiation.

Cell Differentiation↗

PubMed2002

Transcription factor regulation in mammary epithelial cells.

Extracellular hormones, growth factors or cytokines relay their effects on the transcription of genes through the recognition of specific receptors and intracellular signaling molecules. Stat (signal transducers and activators of transcription) have been recognized as crucial intracellular signaling molecules. The cytokine receptor associated Jak kinases convert the latent monomeric form of the Stat molecules to the activated dimeric form through tyrosine phosphorylation. The dimers bind to specific DNA response elements and are able to induce transcription. The transcription factor Stat5 is a central determinant of mammary gland development and function. It is activated during pregnancy by prolactin and contributes to the growth and alveolar differentiation of the epithelial cells. During lactation it governs milk protein gene expression and contributes to cell survival. Negative regulatory potential is exerted by the expression of the short form of the molecule, lacking the transactivation domain, but associating with nuclear co-repressors. This form is activated through tyrosine phosphorylation and dimerisation similarly to the full-length form, but is impeded in dephosphorylation and co-activator recruitment. Positive enhancement of Stat5 transactivation potential is provided by the glucocorticoid receptor (GR). Ligand activation of the receptor causes complex formation with Stat5 and deviation to the Stat5 DNA binding site. An additional regulatory loop is provided by the reactivation of the short form of Stat5 through GR association.

Animals↗

PubMed2002

Overexpression and forced activation of stat5 in mammary gland of transgenic mice promotes cellular proliferation, enhances differentiation, and delays postlactational apoptosis.

Signal transducer and activator of transcription 5 (Stat5) transduces extracellular cytokine and growth factor signals to the nucleus of mammary epithelial cells and thereby regulates gene transcription during pregnancy, lactation, and weaning. Gene constructs were prepared which subject the wild-type Stat5 or a constitutively active variant of Stat5 to the control of the beta-lactoglobulin (BLG) regulatory sequences and direct it to the mammary epithelium. The integrity and functionality of these constructs were confirmed through introduction into cultured mammary epithelial cells and hormone induction experiments. Expression levels and states of activity of Stat5 in mammary gland tissue were manipulated by introducing Stat5 variants as transgenes into the pronuclei of transgenic mice. The consequences of enhanced Stat5 expression and activation on the development of alveoli, their differentiated functions, and on postlactational involution were investigated. As expected, the transgenic mouse lines expressed the wild-type Stat5 construct (BLG/STAT5) and the constitutively active Stat5 variant (BLG/STAT5ca) exclusively in mammary epithelial cells during pregnancy and lactation. BLG/STAT5 mice exhibited larger alveoli at mid-pregnancy and a delayed onset of involution. Condensed alveoli, a high degree of cellular proliferation, and delayed involution were associated with STAT5ca expression. Elevated levels of beta-casein gene expression were found in BLG/STAT5 and STAT5ca transgenic mice during late pregnancy and lactation, indicating a limiting role for Stat5 under normal physiological conditions. This was accompanied by higher levels of beta-casein secretion into the milk and enhanced growth of pups. Transgenic animals expressing the BLG/STAT5ca transgene were predisposed to tumor formation in the mammary gland. This study extends the functional observations made in cultured mammary epithelial cells and in gene knockout mice. It identifies Stat5 as a multifunctional regulator of mammary cell proliferation, milk protein gene expression, and postlactational apoptosis.

Animals↗