The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/- mice, Sufu+/- mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/- animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/-p53-/- animals resulted from Sufu loss of heterozygosity. Sufu+/-p53-/- medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.

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The MLL gene is frequently rearranged in leukemias, and MLL chimeric proteins generated by chromosomal translocations play crucial roles in leukemogenesis. Targets

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To determine direct effects of epinephrine on adrenal cortisol secretion, bilateral adrenal glands were isolated from guinea pigs, together with bilateral kidneys, aorta, and inferior caval vein for influent and effluent routes. The preparation was perfused with oxygenated Krebs-Ringer bicarbonate solution (pH 7.4) containing 10 mM glucose, 0.2% bovine serum albumin, and 4.6% dextran. The perfusate cortisol level was elevated by the addition of epinephrine in a dose-dependent manner at concentrations greater than 100 pg/ml and increased eightfold as high as the basal level at 1 micrograms/ml epinephrine. The stimulatory effect of epinephrine on cortisol secretion was completely abolished by phentolamine, an alpha-adrenergic antagonist but was not affected by propranolol, a beta-adrenergic antagonist. These results demonstrate that epinephrine has a direct stimulatory effect on adrenal cortisol secretion via an alpha-adrenergic mechanism and also suggest that not only adrenocorticotropin but also epinephrine is a most important factor for the regulation of cortisol secretion.

The effects of arterial-portal glucose difference on the gluconeogenesis from lactate were studied using the bivascular perfused liver isolated from the fasted rat. The liver was cyclically perfused at flow rates of 14 ml/min from the portal vein and of 7 ml/min from the hepatic artery with the total volume of 35 ml of perfusion medium containing 2 mM glucose, 3 mM lactate and (U-14C)-lactate for 20 min. Glucose was infused at a rate of 27.75 mumol/min into the arterial cannula (A-experiment) or the portal cannula (P-experiment), making each arterial-portal glucose gradient of +3.96 mM (arterial glucose > portal glucose) and -1.98 mM (arterial glucose < portal glucose) throughout the experiment. Perfusate lactate concentration was lower in A-experiment than in P-experiment (1.40 +/- 0.25 vs 1.93 +/- 0.23 mM at 20 min, mean +/- SD, p < 0.05). Incorporation of radioactivity from (U-14C)-lactate into glucose carbon 1 in perfusate was 5.7 +/- 0.8% of total radioactivity per 20 min in A-experiment vs 2.8 +/- 0.6%/20 min in P-experiment (p < 0.01). These results suggest that the arterial-portal glucose difference is an important factor to regulate the hepatic gluconeogenesis.

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