Insulin-like growth factor II (IGF-II) is a peptide growth factor that is homologous to both insulin-like growth factor I (IGF-I) and insulin and plays an important role in embryonic development and carcinogenesis. IGF-II is believed to mediate its cellular signaling via the transmembrane tyrosine kinase type 1 insulin-like growth factor receptor (IGF-I-R), which is also the receptor for IGF-I. Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II. In most cells and tissues, IR binds IGF-II with relatively low affinity. The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11. In the present study we found that IR-A but not IR-B bound IGF-II with an affinity close to that of insulin. Moreover, IGF-II bound to IR-A with an affinity equal to that of IGF-II binding to the IGF-I-R. Activation of IR-A by insulin led primarily to metabolic effects, whereas activation of IR-A by IGF-II led primarily to mitogenic effects. These differences in the biological effects of IR-A when activated by either IGF-II or insulin were associated with differential recruitment and activation of intracellular substrates. IR-A was preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney and had a relatively increased proportion of isoform A. IR-A expression was also increased in several tumors including those of the breast and colon. These data indicate, therefore, that there are two receptors for IGF-II, both IGF-I-R and IR-A. Further, they suggest that interaction of IGF-II with IR-A may play a role both in fetal growth and cancer biology.

No abstract

No abstract

Measurements provide the basis for monitoring and control of industrial processes as well as model development and validation. Therefore, systematic approaches are of great value to increase accuracy and reliability of measurements. In bioprocesses, linear conservation relations such as elements and enthalpy can be employed to relate conversion rates. In this work, a systematic approach has been applied to production scale fed‐batch yeast fermentations. The six data sets obtained from two industrial size bubble columns, one with 25 m3 volumes and the other with 100 m3 volumes, are analyzed for state estimation and error diagnosis. A statistical test is employed for error diagnosis. The serial elimination method is used to analyze and locate the source of errors. The conversion rates are calculated from primary measurements such as flow rates, temperatures, and concentrations. When available measurements are more than the degrees of freedom of the system, it is said that the system is redundant. The redundancy is, therefore, used for error detection and data reconciliation for the six data sets in this work. In addition to elemental balances, heat balance has been set up for the bubble columns, and metabolic heat production rate is employed as an additional measurement. The redundancy is employed for state estimation, and biomass concentration and specific growth rate have been estimated with great accuracy. The estimations can be further used for process monitoring and control. © 2006 American Institute of Chemical Engineers AIChE J, 2006

No abstract

Malignant mesothelioma is a deadly disease with limited therapeutic options. EphB4 is an oncogenic tyrosine kinase receptor expressed in malignant mesothelioma as well as in a variety of cancers. It is involved in tumor microenvironment mediating angiogenesis and invasive cellular effects via both EphrinB2 ligand-dependent and independent mechanisms. The molecular network underlying EphB4 oncogenic effects is still unclear. Here we show that EphB4 expression in malignant mesothelioma cells is markedly decreased upon neutralization of cancer-secreted IGF-II. In particular, we demonstrate that EphB4 protein expression in malignant mesothelioma cells depend upon a degradation rescue mechanism controlled by the autocrine IGF-II-insulin receptor-A specific signaling axis. We show that the regulation of EphB4 expression is linked to a competing post-translational modification of its carboxy-terminal tail via phosphorylation of its tyrosine 987 by the Insulin receptor isoform-A kinase-associated activity in response to the autocrine IGF-II stimuli. Neutralization of this autocrine-induced EphB4-phosphorylation by IGF-II associates with the increased ubiquitination of EphB4 carboxy-terminal tail and with its rapid degradation. We also describe a novel Ubiquitin binding motif in the targeted region as part of the identified EphB4 phosphodegron and provide 3D modeling data supporting a possible model for the acute EphB4 PTM-driven regulation by IGF-II. Altogether, these findings disclose a novel molecular mechanism for the maintenance of EphB4-expression in malignant mesothelioma cells and other IGF-II-secreting cancers (IGF2omas).

Control of ribosome biogenesis is a potential mechanism for the regulation of cell size during growth, and a key step in regulating ribosome production is ribosomal RNA synthesis by RNA polymerase I (Pol I). In humans, Pol I transcription requires the upstream binding factor UBF and the selectivity factor SL1 to assemble coordinately on the promoter. UBF is an HMG box-containing factor that binds to the rDNA promoter and activates Pol I transcription through its acidic carboxy-terminal tail. Using UBF (284-670) as bait in a yeast two-hybrid screen, we have identified an interaction between UBF and TAF1, a factor involved in the transcription of cell cycle and growth regulatory genes. Coimmunoprecipitation and protein-protein interaction assays confirmed that TAF1 binds to UBF. Confocal microscopy showed that TAF1 colocalizes with UBF in Hela cells, and cell fractionation experiments provided further evidence that a portion of TAF1 is localized in the nucleolus, the organelle devoted to ribosomal DNA transcription. Cotransfection and in vitro transcription assays showed that TAF1 stimulates Pol I transcription in a dosage-dependent manner. Thus, TAF1 may be involved in the coordinate expression of Pol I- and Pol II-transcribed genes required for protein biosynthesis and cell cycle progression.

No abstract