br Particle swarm optimization for
Particle swarm optimization for NLBP
Acknowledgements This work was supported by the State Key Development Program for Basic Research of China (No. 2009CB421104) and the National Natural Science Foundation of China (Nos. 50809004 & 41071323).
Main Text It has been more than 30 years since constitutively active mutant forms of KRAS, HRAS, and NRAS were shown to transform cells in culture, thus suggesting their ability to drive tumorigenesis autonomously. Indeed, it is now known that mutations in these genes contribute to loss of growth control in approximately 30% of all human cancers (Pylayeva-Gupta et al., 2011). However, detailed analyses of the growth factor signaling pathways impacted by RAS later demonstrated that wild-type (WT) RAS isoforms play a significant role in the transformative abilities of oncogenic RAS mutants (Huang et al., 1993, Lim et al., 2008, Young et al., 2013), but the molecular mechanism remained unknown. In this issue of Cancer Cell, Grabocka et al. (2014) provide a major advance in understanding the relationship between oncogenic RAS and WT RAS isoforms in tumorigenesis by elucidating how expression of WT RAS isoforms affect both tumor progression and chemotherapeutic sensitivity by modulating the DNA damage response. To examine the contribution of WT RAS isoforms in promoting tumorigenesis in KRAS-driven tumors, Grabocka et al. (2014) first use WT KRAS and mutant KRAS (G12D) pancreatic and colon carcinoma cells engineered for inducible suppression of WT HRAS and NRAS expression. They show that silencing of HRAS or NRAS in mutant-KRAS cells increases MAPK-RSK and PI3K-AKT signaling and delays progression through G2/M phase, but has no effect on cells expressing WT KRAS. Furthermore, no substantial change in this delay was observed when both HRAS and NRAS were concurrently depleted, suggesting that HRAS and NRAS function within a single module to regulate oncogenic KRAS signaling. Together with previous studies, these results demonstrate that HRAS and NRAS work to limit oncogenic signaling, which, in turn, leads to Imiquimod receptor delays. The delayed cell cycle progression and mitotic defects observed upon WT RAS isoform suppression are consistent with the well-established effect of oncogenic signaling on genomic instability and cell cycle checkpoint activation. Oncogenic RAS expression, like most oncogenes, causes replication stress, which is defined as the DNA damage response (DDR) associated with perturbed S phase progression, and leads to the activation of the ATR and ATM kinases (Halazonetis et al., 2008). Engagement of the DDR initially acts as a barrier to tumorigenesis by inducing cell cycle arrest, senescence, or apoptosis. However, as tumors evolve, attenuation or loss of specific components of the DDR, such as p53, suppresses these outcomes, thus affording tumor progression. CHK1, a checkpoint kinase operating directly downstream of ATR, has been shown in some cases to be inhibited by growth factor signaling pathways through phosphorylation on S280, which prevents CHK1 activation via phosphorylation of S317 and S345 by ATR (King et al., 2004). Therefore, S280 phosphorylation of CHK1 is one mechanism among many by which the oncogenic stress-induced checkpoint response can be compromised. However, checkpoint abrogation can be a double-edged sword, allowing cell cycle progression but further promoting genomic instability. Grabocka et al. (2014) demonstrate that depletion of HRAS or NRAS leads to an increase in inhibitory phosphorylation of CHK1 at S280 and a decrease of phospho-CHK1 at S317 and S345 without affecting the ATM-CHK2 signaling pathway. Consistent with checkpoint mitigation after suppression of WT RAS isoforms, KRAS mutant cells failed to block mitotic entry soon after exogenous DNA damage. Because the long-term effects of checkpoint abrogation can be genome destabilizing, these results are in agreement with the observed mitotic defects and increased phosphorylation of the histone variant H2AX (γH2AX) when WT RAS isoforms were suppressed in mutant RAS-transformed cells. These findings indicate that oncogene-enforced limitation of DNA damage checkpoint control may promote additional genomic instability in affected tumors (Figure 1).