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MR Schneider, E Wolf, A Hoeflich, and H Lahm

The multiple activities of IGF-I and -II are modulated by a family of IGF-binding proteins (IGFBP-1 to -6). Although structurally related, each IGFBP has unique properties and exerts specific functions. IGFBP-5 is the most conserved IGFBP across species and was identified as an essential regulator of physiological processes in bone, kidney and mammary gland. In addition, IGFBP-5 appears to play a decisive role in the control of proliferation of specific tumour cell types. In many situations IGFBP5 exerts biological activities in the absence of IGFs, indicating the existence of IGF-independent actions. This concept was supported by the unexpected localisation of IGFBP-5 in the nucleus and the description of IGFBP-5-specific membrane-bound IGFBP-5 receptor(s). The scope of this review is to summarise the available information about the structure of IGFBP-5 and the regulation of its expression. Furthermore, the potential significance of IGFBP-5 in the regulation of physiological processes will be critically analysed in the light of recent experimental data.

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R Zhou, D Diehl, A Hoeflich, H Lahm, and E Wolf

IGFs have multiple functions regarding cellular growth, survival and differentiation under different physiological and pathological conditions. IGF effects are modulated systemically and locally by six high-affinity IGF-binding proteins (IGFBP-1 to -6). Despite their structural similarity, each IGFBP has unique properties and exhibits specific functions. IGFBP-4, the smallest IGFBP, exists in both non-glycosylated and N-glycosylated forms in all biological fluids. It is expressed by a wide range of cell types and tIssues, and its expression is regulated by different mechanisms in a cell type-specific manner. IGFBP-4 binds IGF-I and IGF-II with similar affinities and inhibits their actions under almost all in vitro and in vivo conditions. In this review, we summarize the available data regarding the following aspects of IGFBP-4: genomic organization, protein structure-function relationship, expression and its regulation, as well as IGF-dependent and -independent actions. The biological significance of IGFBP-4 for reproductive physiology, bone formation, renal pathophysiology and cancer is discussed.

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J Manolopoulou, M Bielohuby, S J Caton, C E Gomez-Sanchez, I Renner-Mueller, E Wolf, U D Lichtenauer, F Beuschlein, A Hoeflich, and M Bidlingmaier

Data on the involvement of aldosterone in the regulation of the renin–angiotensin–aldosterone system (RAAS) in rodents are still scarce, partly due to the high sample volumes needed by commercially available assays and to the very low aldosterone concentrations present. We have developed a highly sensitive and non-isotopic immunoassay, requiring a volume of only 50 μl serum for a duplicate measurement, employing a highly specific monoclonal antibody against aldosterone. The assay was validated in human and mouse samples and exhibited a linear working range from 10 to 1000 pg/ml. Values obtained after a chromatographic purification step correlated significantly to the dichloromethane extraction ordinarily used. Basal aldosterone values were measured in 75 mouse hybrids and found within the linear range (173±21 pg/ml), with no significant difference between males and females. Additionally, we show an increase in serum aldosterone in mice from 3 to 11 weeks of age. Mice of the same genetic background were treated with dexamethasone intraperitoneally (n=7), resulting in significantly decreased concentrations (35±3 vs 114±33 pg/ml in controls; P<0.001). In contrast, adrenocorticotropic hormone resulted in significantly increased serum aldosterone (603±119 pg/ml; n=7; P<0.001), as did the physiological stimulation of the RAAS by a high K+/low Na+ diet (1369±703 vs 172±36 pg/ml). In conclusion, we have developed and validated an extremely sensitive assay for determination of aldosterone concentrations from very small serum samples, which could be especially useful in pharmacological intervention studies in rodent models.