Abstract
BackgroundThe Retinoblastoma protein (pRB) is a key tumor suppressor that is functionally inactivated in most cancers. pRB regulates the cell division cycle and cell cycle exit through protein–protein interactions mediated by its multiple binding interfaces. The LXCXE binding cleft region of pRB mediates interactions with cellular proteins that have chromatin regulatory functions. Chromatin regulation mediated by pRB is required for a stress responsive cell cycle arrest, including oncogene induced senescence. The in vivo role of chromatin regulation by pRB during senescence, and its relevance to cancer is not clear.Methodology/Principal FindingsUsing gene-targeted mice, uniquely defective for pRB mediated chromatin regulation, we investigated its role during transformation and tumor progression in response to activation of oncogenic ras. We report that the pRB∆L mutation confers susceptibility to escape from HrasV12 induced senescence and allows transformation in vitro, although these cells possess high levels of DNA damage. Intriguingly, LSL-Kras, Rb1 ∆L/∆L mice show delayed lung tumor formation compared to controls. This is likely due to the increased apoptosis seen in the early hyperplastic lesions shortly following ras activation that inhibits tumor progression. Furthermore, DMBA treatment to induce sporadic ras mutations in other tissues also failed to reveal greater susceptibility to cancer in Rb1 ∆L/∆L mice.Conclusions/SignificanceOur data suggests that chromatin regulation by pRB can function to limit proliferation, but its loss fails to contribute to cancer susceptibility in ras driven tumor models because of elevated levels of DNA damage and apoptosis.
Highlights
Oncogene induced senescence (OIS) has emerged as a tumor suppressive mechanism that acts as a barrier to transformation in vivo [1]
The foci in Rb1∆L/∆L cultures were bigger and often formed multilayered aggregates suggestive of loss of contact inhibition, characteristic of immortalized cell clones (Figure 1C). This suggests that the Rb1∆L mutation increases susceptibility to escape from oncogene induced senescence (OIS) and this might lead to spontaneous immortalization in culture
Our study shows that mutation of the LXCXE binding cleft that disrupts chromatin regulation by pRb is sufficient for escape from oncogene induced senescence and transformation in vitro
Summary
Oncogene induced senescence (OIS) has emerged as a tumor suppressive mechanism that acts as a barrier to transformation in vivo [1]. Senescence in these mouse models is predominantly associated with pre-malignant stages of tumorigenesis suggesting a role for senescence in inhibiting or delaying tumor progression in response to oncogene activation in vivo. Senescence is associated with activation of tumor suppressor pathways regulated by p53 and pRB proteins [5,6] These two pathways coordinately inhibit the growth of precancerous cells and prevent them from becoming tumors. Methodology/Principal Findings: Using gene-targeted mice, uniquely defective for pRB mediated chromatin regulation, we investigated its role during transformation and tumor progression in response to activation of oncogenic ras. Conclusions/Significance: Our data suggests that chromatin regulation by pRB can function to limit proliferation, but its loss fails to contribute to cancer susceptibility in ras driven tumor models because of elevated levels of DNA damage and apoptosis
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