Retinoblastoma Function Is Essential for Establishing Lung Epithelial Quiescence after Injury

Abstract

The retinoblastoma gene product (RB) regulates cell cycle, quiescence, and survival in a cell type-dependent and environment-dependent manner. RB function is critical in the pulmonary epithelium, as evidenced by nearly universal RB inactivation in lung cancer and increased lung cancer risk in persons with germline RB gene mutations. Lung carcinomas occur in the context of epithelial remodeling induced by cytotoxic damage. Whereas the role of RB in development and normal organ homeostasis has been extensively studied, RB function in the context of cellular injury and repair has remained largely unexplored. In the current studies, the RB gene was selectively deleted in the respiratory epithelium of the mouse. Although RB was not required for establishing or maintaining quiescence during lung homeostasis, RB was essential for establishing quiescence during epithelial repair after injury. Notably, aberrant cell cycle progression was sustained for 9 months after injury in RB-deficient lungs. Prenatal and postnatal RB ablation had similar effects, providing evidence that timing of RB loss was not critical to the outcome and that the injury-induced phenotype was not secondary to compensatory alterations occurring during development. These data show that RB is essential for repair of the respiratory epithelium after cytotoxic damage and support a critical unique role for RB in the context of epithelial remodeling after injury. Because human cancers are associated with chronic cellular damage, these findings have important new implications for RB-mediated tumor suppression. [Cancer Res 2008;68(11):4068-76]

A G1 Checkpoint Mediated by the Retinoblastoma Protein That Is Dispensable in Terminal Differentiation but Essential for Senescence

“…The unique role for pRB-LXCXE regulation of chromatin in senescence that we describe offers a similar glimpse at a fundamental stress response mechanism. Indeed, other reports have suggested a role for pRB in stress responses (34,37). In particular, lung epithelium appears to use pRB in a very specific role in controlling proliferation following injury, but not in development (37).…”

“…Indeed, other reports have suggested a role for pRB in stress responses (34,37). In particular, lung epithelium appears to use pRB in a very specific role in controlling proliferation following injury, but not in development (37). Thus, it seems that pRB plays a unique role in this growth control paradigm that developed to respond to stressful exogenous stimuli, including DNA damage or the release of TGF-␤ in response to tissue trauma, or as a protective response to chemical toxicity.…”

Stem Cell Biology in the Lung and Lung Cancers: Using Pulmonary Context and Classic Approaches

“…epithelial regeneration. Stimulation and visualization of lung cell proliferation are facilitated by induction of lung injury; normal mouse lung has few to no epithelial cells that are capable of incorporating nucleotide analogs or staining for Ki-67, indicating that the lung epithelia is largely quiescent (Mason-Richie et al 2008). Analyses of existing lung injury models, described below, have led to the identification of some putative lung stem cell populations.…”

Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27KIP1–Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression

“…Due to this interplay between pRB and CDK activity, it has been difficult to place one upstream of the other in a regulatory pathway (4). Numerous studies suggest that either pRB-E2F or p27 KIP1 -CDK2 interactions are essential for controlling quiescence or cell cycle entry commitment (9)(10)(11)(12)(13)(14)(15)(16)(17). For this reason, control of the G 1 -S phase transition remains unclear.…”