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Papers by Birgit Bossenmaier

Cancer Research, 2008

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3973 The epidermal growth factor receptor (E... more AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3973 The epidermal growth factor receptor (EGFR, HER1) is a clinically validated target for unconjugated antibodies in the treatment of cancer. It is over-expressed in a large variety of tumors for example in non-small cell lung cancer (NSCLC), head and neck, colorectal, gastric, pancreatic, renal cell, breast and prostate cancer as well as in gliomas. One anti-EGFR antibody, cetuximab, is already approved for the treatment of refractory metastatic colorectal cancer (mCRC) and of locally advanced and recurrent head and neck cancer. A second EGFR antibody, panitumumab has also been approved for mCRC. Several more EGFR antibodies are currently in clinical development. Response rates and times to progression with these drugs are modest (e.g., 11% and 1.5 months for cetuximab alone and 23 % and 4.1 months in combination with chemotherapy in mCRC) which means there is a significant need to improve on these results. Anti-EGFR antibodies...

European Journal of Biochemistry, 2008

We have previously shown, in rat‐1 fibroblasts which stably overexpress high levels of human insu... more We have previously shown, in rat‐1 fibroblasts which stably overexpress high levels of human insulin receptor (HIR), that high glucose levels induce an inhibition of insulin receptor tyrosine kinase (IRK) activity [Berti, L., Mosthaf, L., Kellerer, M., Tippmer, S., Mushack, J., Seffer, E., Seedorf, K., Häring, H. (1994) J. Biol. Chem. 269, 3381–3386]. This effect appears to be mediated through activation of protein kinase C and phosphorylation of the receptor β‐subunit on threonine or serine residues. The aim of the present study was to determine whether the juxtamembrane region or the C‐terminus tail of the receptor are involved in the IRK modulation by glucose. In these domains increased serine and threonine phosphorylation was observed after phorbol ester or insulin stimulation of cells, and a regulatory function for IRK activity seems conceivable. We used an antibody directed against one potential regulatory site in the C‐terminus tail, i.e. PSer1315, to study the effect of gluc...

PLoS ONE, 2012

Cub domain containing protein 1 (CDCP1) is strongly expressed in tumors derived from lung, colon,... more Cub domain containing protein 1 (CDCP1) is strongly expressed in tumors derived from lung, colon, ovary, or kidney. It is a membrane protein that is phosphorylated and then bound by Src family kinases. Although expression and phosphorylation of CDCP1 have been investigated in many tumor cell lines, the CDCP1 features responsible for transformation have not been fully evaluated. This is in part due to the lack of an experimental system in which cellular transformation depends on expression of exogenous CDCP1 and Src. Here we use retrovirus mediated co-overexpression of c-Src and CDCP1 to induce focus formation of NIH3T3 cells. Employing different mutants of CDCP1 we show that for a full transformation capacity, the intact amino-and carboxy-termini of CDCP1 are essential. Mutation of any of the core intracellular tyrosine residues (Y734, Y743, or Y762) abolished transformation, and mutation of a palmitoylation motif (C689,690G) strongly reduced it. Src kinase binding to CDCP1 was not required since Src with a defective SH2 domain generated even more CDCP1 dependent foci whereas Src myristoylation was necessary. Taken together, the focus formation assay allowed us to define structural requirements of CDCP1/Src dependent transformation and to characterize the interaction of CDCP1 and Src.

European Journal of Cancer, 2012

were treated with MGCD265 and almost complete inhibition of tumor growth was observed. The inhibi... more were treated with MGCD265 and almost complete inhibition of tumor growth was observed. The inhibition of Met phosphorylation in vitro was also associated with the inhibition of phosphorylation of Met in the MKN45 xenografts as assessed by immunohistochemistry. Conclusions: Using an in vitro surrogate bioassay to monitor target inhibition, up to 75% inhibition of Met phosphorylation occurred at MGCD265 exposures reached to-date in patients treated with single agent MGCD265. This degree of inhibition surpassed that observed in the MKN45 xenograft model at exposures of MGCD265 that demonstrated tumor growth inhibition. Dose escalation continues and updates will be provided at the meeting.

Diabetologia, 2000

The tyrosine kinase activity of the human insulin receptor (HIR) is essential for its signalling ... more The tyrosine kinase activity of the human insulin receptor (HIR) is essential for its signalling function [1]. Insulin-induced autophosphorylation of the receptor b-subunit at tyrosine residues in the kinase domain and in the juxtamembrane domain of the receptor b-subunit is critical for autoactivation of the receptor and for substrate phosphorylation [2, 3]. After the rapid insulin-stimulated tyrosine phosphorylation of the receptor b-subunit, there is a delayed insulinstimulated increase of serine and threonine phosphorylation of the receptor b-subunit in intact cells [4±7]. Serine phosphorylation occurs as well on the next level of the insulin signalling chain, i. e. receptor sub-Diabetologia (2000) 43: 443±449

Diabetes, 1995

GLUT4 translocation and activation of glucose uptake in skeletal muscle can be induced by both ph... more GLUT4 translocation and activation of glucose uptake in skeletal muscle can be induced by both physiological (i.e., insulin, nerve stimulation, or exercise) and pharmacological (i.e., phorbol ester) means. Recently, we demonstrated that high glucose levels may mimic the effects of phorbol esters on protein kinase C (PKC) and insulin receptor function (JBiol Chem 269:3381^3386,1994). In this study, we tested whether the previously described effects of phorbol esters on translocation of GLUT4 in myotubes in culture and also in rat skeletal muscle might be mimicked by glucose. We found that stimulation of C 2 C 12 myotubes with both insulin (10~7 mol/1, 5 min) and glucose (25 mmol/1, 10 min) induces a comparable increase of the GLUT4 content in the plasma membrane. To test whether this effect occurs in intact rat skeletal muscle as weD, two different model systems were used. As an in vitro model, isolated rat hindlimbs were perfused for 80 min with medium containing 6 mmol/1 glucose ± insulin (1.6 X 10~9 mmol/1, 40 min) or 25 mmol/1 glucose. As an in vivo model, acute hyperglycemia (>11 mmol/1 glucose, 20 min) was induced in Wistar rats by intraperitoneal injection of glucose under simultaneous suppression of the endogenous insulin release by injection of somatostatin. In both models, subcellular fractions were prepared from hindlimb skeletal muscle, and plasma membranes were characterized by the enrichment of the marker enzyme ctl Na +-K +-ATPase. Acute hyperglycemia in vivo (n = 5) and in vitro (n = 6) induced an increase of GLUT4 content in the a l Na +-K +-ATPase-enriched fraction (in vivo, 2.45 ± 0.47-fold increase to basal [mean ± SE]; in vitro, 1.71 ± 0.14-fold increase to basal), which was quantitatively similar to that obtained after insulin treatment (in vivo, 2.35 ± 0.62-fold increase to basal; in vitro, 1.91 ± 0.21-fold increase to basal). Glucose-induced GLUT4 translocation in myotubes was prevented by prior addition of the PKC inhibitor l-(5-isoquinolinylsulfonyl)-2-methylpiperazine; in rat skeletal muscle,

Experimental and Clinical Endocrinology & Diabetes, 2009