RalGEFs were recently shown to be critical for Ras-mediated transformed and tumorigenic growth of human cells. We now show that the oncogenic activity of these proteins is propagated by activation of one RalGEF substrate, RalA, but blunted by another closely related substrate, RalB, and that the oncogenic signaling requires binding of the RalBP1 and exocyst subunit effector proteins. Knockdown of RalA expression impeded, if not abolished, the ability of human cancer cells to form tumors. RalA was also commonly activated in a panel of cell lines from pancreatic cancers, a disease characterized by activation of Ras. Activation of RalA signaling thus appears to be a critical step in Ras-induced transformation and tumorigenesis of human cells.
Background
The RAS oncogenes (HRAS, NRAS and KRAS) comprise the most frequently mutated class of oncogenes in human cancers (33%), stimulating intensive effort in developing anti-Ras inhibitors for cancer treatment.
Discussion
Despite intensive effort, to date no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer.
Conclusions
Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery.
Digoxin, in the absence of detectable inotropic or hemodynamic effects, caused a reduction in cardiac norepinephrine spillover in patients with heart failure who had elevated filling pressures. This finding suggests a potentially beneficial primary autonomic action of digoxin in patients with severe heart failure.
Endothelial nitric oxide synthase (NOS) and neuronal NOS protein increased in proximal tubules of acidotic diabetic rats 3-5 wk after streptozotocin injection. NOS activity (citrulline production) was similar in nondiabetic and diabetic tubules incubated with low glucose (5 mM glucose + 20 mM mannitol); but after 30 min with high glucose (25 mM), Ca-sensitive citrulline production had increased 23% in diabetic tubules. Glucose concentration did not influence citrulline production in nondiabetic tubules. High glucose increased carboxy-2-phenyl-4,4,5,5,-tetramethylimidazoline 1-oxyl-3-oxide (cpt10)-scavenged NO sevenfold in a suspension of diabetic tubules but did not alter NO in nondiabetic tubules. Diabetes increased ouabain-sensitive 86Rb uptake (141 +/- 9 vs. 122 +/- 6 nmol x min(-1) x mg(-1)) and oligomycin-sensitive O2 consumption (QO2; 16.0 +/- 1.7 vs. 11.3 +/- 0.7 nmol x min(-1) x mg(-1)). Ethylisopropyl amiloride-inhibitable QO2 (6.5 +/- 0.6 vs. 2.4 +/- 0.3 nmol x min(-1) x mg(-1)) accounted for increased oligomycin-sensitive QO2 in diabetic tubules. N(G)-monomethyl-L-arginine methyl ester (L-NAME) inhibited most of the increase in 86Rb uptake and QO2 in diabetic tubules. L-NAME had little effect on nondiabetic tubules. Inhibition of QO2 by ethylisopropyl amiloride and L-NAME was only 5-8% additive. Uncontrolled diabetes for 3-5 wk increases NOS protein in proximal tubules and makes NOS activity sensitive to glucose concentration. Under these conditions, NO stimulates Na-K-ATPase and QO2 in proximal tubules.
This study investigated student learning outcomes using a case-based approach focused on cellular respiration. Students who used the case study, relative to students who did not use the case study, exhibited a significantly greater learning gain, and demonstrated use of higher-order thinking skills. Preliminary data indicate that after engaging with the case study, students were more likely to answer a question addressing misconceptions about cellular respiration correctly when compared with students who did not use the case study. More rigorous testing is needed to fully elucidate whether case-based learning can effectively clarify student misconceptions related to biological processes.
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