The physiological role of IGF-II remains unclear but there is evidence for a role in postnatal growth, the growth of the thymus and bone homeostasis. Glucocorticoids have many effects that are opposite to the effects of IGF-II such as growth retardation, osteoporosis and thymic involution. We therefore wondered whether IGF-II overexpression in transgenic mice might counteract some of the growth inhibitory effects of the glucocorticoid, dexamethasone (DXM).In a dose-finding study in normal mice, 20 µg DXM/ day caused a significant growth delay. The various organs had a different susceptibility to the growth inhibitory effects of DXM. Most affected were thymus and spleen, followed by liver, skeletal muscle and lumbar vertebrae. The weights of the kidney, tibia, and humerus were not significantly diminished.In a second experiment, the effects of DXM in normal and IGF-II-transgenic animals were compared. The IGF-II serum levels in the transgenic animals were more than 40-fold increased compared with control mice and were decreased by 35% in the DXM-treated group. IGF-I serum levels were identical in both mouse strains and rose slightly after DXM administration in controls. Transgenic mice had higher levels of IGF binding protein species of apparent molecular masses of 41·5 kDa, 30 kDa, and 26·5 kDa. DXM reduced the 24 kDa band in both mice strains. In addition it reduced the bands at 38·5 kDa and 26·5 kDa but only in the transgenic animals.The effect of DXM on body growth was similar in normal and IGF-II-transgenic mice. The weight reduction of the various organs caused by DXM was similar in both types of mice except for the skeleton. The weight of the tibia and the humerus were significantly higher in the DXM-treated transgenic mice.In conclusion, we speculate that overexpression of IGF-II in mice partially protects bone from the osteopenic effects of glucocorticoids.

The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.

Homozygous chromosome 9p deletions in gliomas commonly include the CDKN2A and CDKN2B genes, which code for the structurally highly homologous cdk inhibitors/tumor suppressors p16 and p15, respectively. Alternative splicing of the CDKN2A gene results in the expression of p14(ARF). Interestingly, not only p16 and p15, but also the structurally unrelated p14(ARF) appear to function as negative cell cycle regulators. Concerted inactivation of p16, p15 and p14(ARF) could be demonstrated in seven of nine glioblastoma cell lines. Strong suppression of tumorigenicity after transfection with p16 and p15 alone or in combination was seen in cell lines containing neither endogenous p16 nor p15 but functional pRB. Significantly weaker growth suppression was observed in tumors either retaining expression of both p16 and p15 or p15 only. p14(ARF) proved to be a potent tumor suppressor in the presence of wild-type p53, while mutant p53 substantially reduced growth inhibition by p14(ARF). No differences between p16 and p15 effects could be observed, suggesting a largely overlapping function of p16 and p15. To facilitate further research into p16/p15 effects, three cell lines with conditional, tetracycline-controlled p16 expression were established. Reversible growth suppression mediated by p16 was observed in these models. Combined inactivation of CDKN2A and CDKN2B, i.e., loss of both p16 and p15 as well as p14(ARF), results in disruption of two major growth control pathways involving pRB and p53 in malignant gliomas. Therefore, homozygous co-deletions of CDKN2A and CDKN2B rather than mutations targeting individual transcripts are frequently selected for in these tumors.

In addition to cytoreductive surgery, most patients with malignant gliomas also undergo radio-and chemotherapy. An improved understanding of the molecular genetic mechanisms underlying the radio-and chemosensitivity of gliomas may help to identify glioma patients who will benefit from aggressive and, therefore, potentially toxic adjuvant treatment. It may also allow for the development of new therapies aimed at improving the response of these tumors towards chemo-and radiotherapy. The INK4a gene products, p16 and p14ARF, have been suggested as potential regulators of glioma chemo-and radiosensitivity. We have used tetracycline controlled expression of p16 and plasmid-based p14ARF expression to study the chemo-and radiosensitivity of glioma cell lines. Ectopic p16 sensitized U-87MG cells towards treatment with vincristine and possibly also BCNU by approximately 1.5 to 2-fold, and towards ionizing radiation by a factor of 1.5. p14ARF expression was found to render U-87MG cells 2-fold more radioresistant than controls. These findings support a role for p16 and p14ARF as modulators of the radio-and chemosensitivity of gliomas. Further studies of the role of cell cycle regulators in glioma chemo-and radio-sensitivity seem warranted. We would like to point out that such candidate genes which may code for potent growth suppressors (like p16) or even toxic gene products can be successfully investigated using the approach detailed in this manuscript.