A mitogenic and hormonal signalling network regulate mammalian cell division commitment time.

A basic property of mammalian cells is to retain the mitogenically induced "commitment" to undergo DNA replication even in the absence of stimuli. Recent findings on PGF2 alpha and hormone-induced Swiss 3T3 cell multiplication, reveal that this crucial cell cycle event can be regulated by several signalling mechanisms.

Somatostatin receptor imaging in somatotroph and non-functioning pituitary adenomas: correlation with hormonal and visual responses to octreotide.

OBJECTIVE: A multicentre study was undertaken to determine the value of somatostatin receptor (sst) scintigraphy in predicting hormonal and visual responses to octreotide treatment in GH-secreting and non-functioning pituitary adenomas. SUBJECTS AND METHODS: Somatostatin receptor scintigraphy was performed in 48 patients (19 acromegaly, 29 non-functioning pituitary adenomas with ophthalmological defects). Results were expressed as an uptake index of the pituitary area. A threshold for positivity was determined in 23 subjects considered as controls. Thirty-five patients were treated for 1 month with octreotide (300 micrograms daily). The therapeutic response was assessed on GH and IGF-I suppression or evolution of the ophthalmological defects. The relationships between the somatostatin receptor scintigraphy result, the therapeutic effect of octreotide and in vitro studies performed in 12 tumours were studied. RESULTS: From the results of control subjects the uptake index threshold for positivity was 2. In patients, somatostatin receptor scintigraphy was positive in 64% and there was no relationship between uptake index and tumour size. In GH tumours, somatostatin receptor scintigraphy was positive in 68%; uptake index was related to octreotide-induced GH and IGF I suppression. The positive predictive value was 100% and the negative predictive value was 50%. In vitro studies showed detectable binding sites for somatostatin with sst2 and sst5 expression in the 4 GH tumours studied although somatostatin receptor scintigraphy was negative in 2 cases. In non-functioning pituitary adenomas somatostatin receptor scintigraphy was positive in 62%. Based on visual effects, the positive predictive value was 61% and the negative predictive value was 100%. A wide distribution of somatostatin binding sites was found in 8 non-functioning pituitary adenomas with expression of sst2 only. CONCLUSION: In the conditions of the study, in patients with acromegaly, positive somatostatin receptor scintigraphy predicts a hormonal response but the value of somatostatin receptor scintigraphy is limited by its low negative predictive value. In patients with non-functioning pituitary adenomas, negative somatostatin receptor scintigraphy predicts that there will be no visual improvement during octreotide treatment.

Mevalonate dependency of the early cell cycle mitogenic response to epidermal growth factor and prostaglandin F2 alpha in Swiss mouse 3T3 cells.

Lovastatin (LOV), a hydroxy-methylglutaryl-coenzyme A (HMGCoA) reductase competitive inhibitor, blocks epidermal growth factor (EGF)- or prostaglandin F2 alpha (PGF2 alpha)-induced mitogenesis in confluent resting Swiss 3T3 cells. This inhibition occurs even in the presence of insulin, which potentiates the action of these mitogens in such cells. LOV exerts its effect in a 2-80 microM concentration range, with both mitogens attaining 50% inhibition at 7.5 microM. LOV exerted its effect within 0-8 h following mitogenic induction. Mevanolactone (10-80 microM) in the presence of LOV could reverse LOV inhibition within a similar time period. LOV-induced blockage of PGF2 alpha response is reflected in a decrease in the rate of cell entry into S phase. Neither cholesterol, ubiquinone, nor dolichols of various lengths could revert LOV blockage. In EGF- or PGF2 alpha-stimulated cells, LOV did not inhibit [3H]leucine or [3H]mannose incorporation into proteins, while tunicamycin, an inhibitor of N' glycosylation, prevented this last phenomenon. Thus, it appears that LOV exerts its action neither by inhibiting unspecific protein synthesis nor by impairing the N' glycosylation process. These findings strongly suggest that either EGF or PGF2 alpha stimulations generate early cell cycle signals which induce mevalonate formation, N' glycoprotein synthesis, and proliferation. The causal relationship of these events to various mechanisms controlling the onset of DNA synthesis is also discussed.

Transforming growth factor beta 1, insulin and prostaglandin E1 enhance prostaglandin F2 alpha mitogenic action in Swiss 3T3 cells via separate events.

Transforming growth factor beta 1 (TGF beta 1) had no mitogenic effect in Swiss 3T3 cells, but could increase prostaglandin F2 alpha (PGF2 alpha)-induced DNA synthesis. Insulin, but not prostaglandin E1 (PGE1), further enhanced PGF2 alpha action at low TGF beta 1 concentrations. TGF beta 1 also acted concertedly with the protein kinase C (PKC) activator 1-oleoyl-2-acetylglycerol to induce mitogenesis. Thus, it appears that TGF beta 1 and insulin act via separate signals, while TGF beta 1 and PGE1 might share a common pathway not involving TGF beta 1-mediated prostaglandin synthesis. These results suggest that TGF beta 1 might elicit various signalling mechanisms to enhance PGF2 alpha-triggered events.