Functional overexpression of wild‐type p53 correlates with alveolar cell differentiation in the developing human lung

Abstract

At 15 weeks after conception (a.c.), the human pulmonary acinus is lined by distal low-columnar and more proximal cuboidal cells that are successive stages in alveolar type II cell differentiation (pseudoglandular period of lung development). From 16 weeks a.c. onward, there are also 'flatter' cells that are intermediate stages in the differentiation of cuboidal type II cells into squamous type I cells (canalicular period). We investigated the role of wild-type p53 protein and the proliferation marker Ki-67 in the differentiation of type II and type I cells in these two periods. Serial sections from fetal lungs (n ϭ 30) were immunoincubated with antibodies against p53 and Ki-67. The presence of prospective type II and type I cells was confirmed using immunohistochemistry for surfactant protein SP-A as a differentiation marker and light and electron microscopy. The p53 and Ki-67 positive nuclei were quantified per alveolar cell phenotype (i.e., lowcolumnar; cuboidal; flatter). The occurrence of cell apoptosis was studied using propidium iodide (PI) and 4Ј,6Ј-diamino-2-phenylindol dihydrochloride (DAPI) staining. The combined increase in p53 expression and decrease in Ki-67 expression during alveolar epithelial cell differentiation suggests that wild-type p53 protein plays a role in the differentiation of alveolar type II and type I cells in the human lung, and that this function is mediated through cell cycle arrest. The rare incidence of apoptotic nuclei in alveolar type II cells, together with their absence in alveolar type I cells, supports the view that p53 is involved in the differentiation, rather than the death, of alveolar epithelial cells.

miRNA regulated pathways in late stage murine lung development

“…In particular, miR-486, miR-24, miR-182, miR-615-3p and miR-125a-5p are regulated by Tp53 (Figure  2; Additional file 4). Little is known about the functions of Tp53 and MAP2K4 during lung development, though it is thought that p53 may be involved in alveolar epithelial cell differentiation [38]. …”

Hyperoxic Ventilated Premature Baboons Have Increased p53, Oxidant DNA Damage and Decreased VEGF Expression

“…Although p53 null mutant mice have no apparent pulmonary defects, p53 has been linked to the differentiation of the distal airspace epithelium (30). In adult mice, hyperoxia induces alveolar epithelial p53 expression (24).…”

“…The mechanism of p53 inhibition of VEGF expression involves HIF-1 and Sp-1, transcription factors that regulate VEGF gene transcription (25,29). Very little is known about p53 in lung development, but it may be related to differentiation of the normal alveolar epithelium (30). In oxidant lung injury, p53 may inhibit cell proliferation by induction of p21 CIP1/WAF1 (hereafter p21) to allow repair of DNA damage (31).…”

NGF-mediated transcriptional targets of p53 in PC12 neuronal differentiation

“…Transcriptional activity of p53 plays a direct role in embryonic stem cell differentiation by suppression of the Nanog gene [20], and can directly induce Xenopus homebox gene expression [21]. Involvement of p53 has also been shown in spermatogenesis [22], eye development [23] renal development [24], osteogenesis [25], immune development [26], lung development [27] and muscle differentiation [28]. Despite data supporting the transcriptional activity of p53 protein in differentiation, few genetic targets have been described and fewer still within a neuronal context.…”