The p44/wdr77-dependent cellular proliferation process during lung development is reactivated in lung cancer.
During lung development, cells proliferate for a defined length of time before they begin to differentiate. Factors that control this proliferative process and how this growth process is related to lung cancer are currently unknown. Here, we found that the WD40-containing protein (p44/wdr77) was expressed in growing epithelial cells at the early stages of lung development. In contrast, p44/wdr77 expression was diminished in fully differentiated epithelial cells in the adult lung. Loss of p44/wdr77 gene expression led to cell growth arrest and differentiation. Re-expression of p44/wdr77 caused terminally differentiated cells to re-enter the cell cycle. Our findings suggest that p44/wdr77 is essential and sufficient for proliferation of lung epithelial cells. P44/Wdr77 was re-expressed in lung cancer, and silencing p44/wdr77 expression strongly inhibited growth of lung adenocarcinoma cells in tissue culture and abolished growth of lung adenocarcinoma tumor xenografts in mice. The growth arrest induced by loss of p44/wdr77 expression was partially through the p21-Rb signaling. Our results suggest that p44/wdr77 controls cellular proliferation during lung development, and this growth process is reactivated during lung tumorigenesis.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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D000230:Adenocarcinoma / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000196:embryology* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C478359:WDR77 protein, human