Abstract
One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.
Highlights
Small GTPases from the Ras family are well-known molecular switches, that play a pivotal role in the regulation of nearly every cellular process; ranging from cellular growth, differentiation and survival to chemotaxis, transport and apoptosis [1,2,3,4,5,6,7]
Nore1a regulates cellular motility, cell cycle control, apoptosis, and stability of microtubules, whereas Nore1b is rather implicated in adaptive immune defense [72]
Besides MST1, Rassf1a interacts with modulator of apoptosis 1 (MOAP1), a proapoptotic kinase known to bind to Bax, modulating its activity
Summary
Small GTPases from the Ras family are well-known molecular switches, that play a pivotal role in the regulation of nearly every cellular process; ranging from cellular growth, differentiation and survival to chemotaxis, transport and apoptosis [1,2,3,4,5,6,7]. GTP loading increases the affinity of Ras proteins to a plethora of downstream effectors, e.g., PI3K or Raf, resulting in the activation of various pathways. GTP loading is enhanced by guanine nucleotide exchange factors (GEFs), leading to Ras activation whereas GTPase activating proteins (GAPs) accelerate the GTP to GDP hydrolysis, promoting Ras protein deactivation [8]. There is no doubt about these survival-promoting functions, an exciting new image of Ras signaling arose during the last decade; connecting Ras activation with the promotion of apoptosis and other forms of cell death under certain cellular and environmental conditions. Like Ras, its homologue Rheb is associated with cellular growth, protein biosynthesis, translation and regeneration [19,20], actions mediated mainly via activation of its downstream target mTor [21]. This review seeks to summarize the past and recent findings on HRas and Rheb triggered apoptosis, to contribute to a better understanding of these ambivalently signaling oncogenes
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