Altered Regulation of G1 Cyclins in Oxidant-induced Growth Arrest of Lung Alveolar Epithelial Cells

Abstract

The alveolar surface of the lung is a major target for oxidant injury, and its repair following injury is dependent on the ability of its stem cells, the type 2 cells, to initiate proliferation. From previous studies it is likely that events located before the entry into the S phase of the cell cycle and involving several components of the insulin-like growth factor system as well as of transforming growth factor-␤ (TGF-␤) play a key role in growth regulation of oxidant-exposed type 2 epithelial cells. To gain further insights into these mechanisms, we explored the effects of O 2 exposure on G 1 cyclins and their cyclin-dependent kinases (CDKs). We documented an increased expression of these genes in O 2 -treated type 2 cells. However, despite this induction, a dramatic decrease in cyclin E-CDK2 activity, but not in cyclin D-CDK4 activity, was found. The concomitant induction of CDK inhibitory proteins (CKIs), mainly p21 CIP1 , suggests that accumulation of inactive cyclin E-CDK2 activity is due to CKI binding. We also provided evidence that the mechanisms regulating this process involved TGF-␤ as anti-TGF-␤ antibody treatment was able to reduce the oxidant-induced inhibition of cyclin E-CDK2 activity. Taken together, these results suggest that oxidants may block entry into S phase by acting on a subset of late G 1 events whose alterations are sufficient to impair the activation of cyclin E-CDK2 complexes.

Hyperoxia Induces Macrophage Cell Cycle Arrest by Adhesion-dependent Induction of p21Cip1 and Activation of the Retinoblastoma Protein

“…p21 has also been shown to play a crucial role in cell cycle control in response to the other stimuli such as glucocorticoids (22) and cigarette smoke (23). In lung epithelial cells, a marked increase in p21 has been observed after oxygen exposure (15). A study by Corroyer et al (15) found that one target of p21 action was the cyclin E-CDK2 complex that facilitates cell cycle progression to the S phase (15).…”

“…In lung epithelial cells, a marked increase in p21 has been observed after oxygen exposure (15). A study by Corroyer et al (15) found that one target of p21 action was the cyclin E-CDK2 complex that facilitates cell cycle progression to the S phase (15). Induction of p21 can occur via p53-dependent (24,25) and p53-independent mechanisms (26 -29).…”

“…In epithelial cells, hyperoxia inhibits proliferation through activation of cell cycle checkpoints until DNA damage is repaired. This phenomenon is critical for maintaining genomic integrity (3,5,15). Various proteins are known to be key regulators of the cell cycle, including cyclins, cyclin-dependent kinases (CDK), 1 and CDK inhibitors (CKI).…”

Neutrophil elastase inhibition of cell cycle progression in airway epithelial cells in vitro is mediated by p27kip1

“…In response to ROS treatment, p21 has been shown to inhibit cyclin-CDK2 activity in alveolar epithelial cells and arrest the cell cycle (7). Similarly, in mice exposed to hyperoxia, there is accumulation of p21 in both the bronchiolar and alveolar epithelium that decreases over time during the recovery period (32).…”

Increase in p21 expression independent of the p53 pathway in bleomycin-induced lung fibrosis

“…The p53 pathway was found to be involved upon exposure of lung epithelial cells to either hyperoxia (Barazzone et al, 1998;McGrath, 1998;O'Reilly et al, 1998) or to a number of DNA-damaging agents and carcinogens (Corroyer et al, 1996;Fujishita et al, 1995;Gadbois and Lehnert, 1997;Guinee et al, 1996). The expression of p16 (Sabourin et al, 1998), p21 (Guinee et al, 1996;McGrath, 1998), Rb (Fujishita et al, 1995;Sabourin et al, 1998), c-jun (Dolan et al, 1994;Haase et al, 1997), c-Fos (Haase et al, 1997), TNF-a (Lee and Rannels, 1998;Yao et al, 1998), TGFh (Lee and Rannels, 1998), BAX (Guinee et al, 1997), and Bcl-2 (Guinee et al, 1997) was reported to be influenced by a number of DNA-damaging agents and pollutants but the exact mechanism is still unclear.…”