p38α MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation

Abstract

Stem cell function is central for the maintenance of normal tissue homeostasis. Here we show that deletion of p38alpha mitogen-activated protein (MAP) kinase in adult mice results in increased proliferation and defective differentiation of lung stem and progenitor cells both in vivo and in vitro. We found that p38alpha positively regulates factors such as CCAAT/enhancer-binding protein that are required for lung cell differentiation. In addition, p38alpha controls self-renewal of the lung stem and progenitor cell population by inhibiting proliferation-inducing signals, most notably epidermal growth factor receptor. As a consequence, the inactivation of p38alpha leads to an immature and hyperproliferative lung epithelium that is highly sensitized to K-Ras(G12V)-induced tumorigenesis. Our results indicate that by coordinating proliferation and differentiation signals in lung stem and progenitor cells, p38alpha has a key role in the regulation of lung cell renewal and tumorigenesis.

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

“…8,49 In contrast, in this study, we show a significant reduction in K-ras-induced lung tumours in P224I p38MAPK mice. In addition, these mice appeared to be more sensitive to cisplatin treatment.…”

“…41,42 Although the direct correlation between expression of cyclophilins and phosphorylation of p38MAPK has not been established, increased levels of phosphorylated p38MAPK have been described in various cancers. 8,9,[12][13][14]35,43 In this study, we found that cyclophilinmediated isomerisation could be a critical step in the activation of p38MAPK, which could explain the correlative evidence in the literature concerning the overexpression of cyclophilins and an increase in p38MAPK phosphorylation. This in turn could suggest that different cyclophilins and in particular CypA can function as a molecular switch to modulate p38MAPK signalling to adjust to environmental changes, thus modulating cancer cell survival.…”

“…[3][4][5][6] Initial experiments using mouse models of cancer showed that p38MAPK suppresses lung and liver tumour formation in vivo. 7,8 However, enhanced p38 phosphorylation also correlates with poor prognosis in some patients with breast cancer and hepatocellular carcinoma. 9,10 Similarly, overexpression or activation of p38MAPK has been reported in lymphomas, thyroid neoplasms and human lung tumours.…”

MAPK signaling in inflammation-associated cancer development

“…During myoblast differentiation, p38α regulates the SWI-SNF chromatin-remodeling complexmediated muscle-specific gene expression . In adult lung tissue, p38α activation is essential to maintain the cell differentiation as well as to restrain proliferation of lung stem and progenitor cells (Ventura et al, 2007).…”

“…The tumor suppressive role of p38 has been demonstrated in lung cancer development. A study applying conditional deletion of p38α in adult mice showed that K-Ras G12V -induced lung tumorigenesis was markedly increased in mutant mice, due to hyperproliferation of lung epithelium and progenitor cells (Ventura et al, 2007). Mice mutated in other components of this pathway revealed similar tumor suppressive functions of p38.…”