κB-Ras Proteins Regulate Both NF-κB-Dependent Inflammation and Ral-Dependent Proliferation

Abstract

Transformation of cells generally involves multiple genetic lesions that undermine control of both cell death and proliferation. We now report that κB-Ras proteins act as regulators of NF-κB and Ral pathways, which control inflammation/cell death and proliferation, respectively. Cells lacking κB-Ras therefore not only show increased NF-κB activity, that results in increased expression of inflammatory mediators, but also exhibit elevated Ral activity, that leads to enhanced anchorage-independent proliferation (AIP). κB-Ras deficiency consequently leads to significantly increased tumor growth that can be dampened by inhibiting either Ral or NF-κB pathways, revealing the unique tumor suppressive potential of κB-Ras proteins. Remarkably, numerous human tumors show reduced levels of κB-Ras, and increasing the level of κB-Ras in these tumor cells impairs their ability to undergo AIP, thereby implicating κB-Ras proteins in human disease.

Bridging the gap: A regulator of NF-κB linking inflammation and cancer

“…We created a κB-Ras knock-out mouse to further investigate the role of κB-Ras in inflammation and found that in response to NF-κB activation by lipopolysaccharide (LPS), macrophages lacking κB-Ras expressed higher levels of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) than wild-type macrophages. Consistent with this observation, κB-Ras-deficient mice were hypersensitive to LPS-induced shock and perished significantly faster than wild-type controls [23]. Surprisingly, we found in the same study that κB-Ras proteins have another, completely unrelated cellular interaction partner: Ral-GAP, the complex negatively regulating the Ral GTPase.…”

“…We found that cells lacking both isoforms of κB-Ras had increased levels of GTP-bound Ral (“on”), indicating that κB-Ras enhances Ral-GAP activity and serves as a negative regulator of Ral signaling (Figure 2). Consistent with this observation, immortalized fibroblasts deficient for κB-Ras exhibited a strong increase in AIP as well as enhanced tumor growth when implanted into immunodeficient mice [23]. Taken together, these data demonstrate that κB-Ras is an active regulator of NF-κB signaling and Ras/Ral signaling, making it the only known molecular bridge between these two cancer-relevant pathways (Figure 4).…”

“…through RAS signaling) and the extrinsic pathway (through NF-κB signaling) are generally considered to be independent of each other. Recently, however, we reported that the NF-κB inhibitor-interacting Ras-like (κB-Ras) proteins actively regulate both NF-κB signaling and RAS signaling [23]. The κB-Ras proteins, κB-Ras 1 and κB-Ras 2, are small GTPases in the Ras family that appear to be locked constitutively in a GTP-bound state [24,25].…”

“…Taken together, these data demonstrate that κB-Ras is an active regulator of NF-κB signaling and Ras/Ral signaling, making it the only known molecular bridge between these two cancer-relevant pathways (Figure 4). The biological relevance of this central position is underscored by the observation that expression levels of κB-Ras are reduced in a wide variety of human cancers, including oral cancer [23,32]. Intriguingly, human cancer cell lines carrying an oncogenic RAS mutation had consistently lower protein levels of κB-Ras than similar cell lines encoding wild-type RAS .…”

“…Intriguingly, human cancer cell lines carrying an oncogenic RAS mutation had consistently lower protein levels of κB-Ras than similar cell lines encoding wild-type RAS . Restoring κB-Ras protein levels in two of these cell lines by transfection reduced their ability for anchorage-independent growth [23]. …”