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The p44/wdr77-dependent cellular proliferation process during lung development is reactivated in lung cancer

Oncogene volume 32, pages 1888–1900 (2013)Cite this article

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Abstract

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.

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References

  1. Herbst RS, Heymach JV, Lippman SM . Lung cancer. N Engl J Med 2008; 359: 1367–1380.

    Article  CAS  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Cardoso WV . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  PubMed  Google Scholar 

  3. Warburton D, Schwarz M, Tefft D, Flores-Delgado G, Anderson KD, Cardoso WV . The molecular basis of lung morphogenesis. Mech Dev 2000; 92: 55–81.

    Article  CAS  PubMed  Google Scholar 

  4. Mendelson CR . Role of transcription factors in fetal lung development and surfactant protein gene expression. Annu Rev Physiol 2000; 62: 875–915.

    Article  CAS  PubMed  Google Scholar 

  5. Shi W, Xu J, Warburton D . Development, repair and fibrosis: what is common and why it matters. Respirology 2009; 14: 656–665.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hosohata K, Li P, Hosohata Y, Qin J, Roeder RG, Wang Z . Purification and identification of a novel complex which is involved in androgen receptor-dependent transcription. Mol Cell Biol 2003; 23: 7019–7029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhou L, Wu H, Lee P, Wang Z . Roles of the androgen receptor cofactor p44 in the growth of prostate epithelial cells. J Mol Endocrinol 2006; 37: 283–300.

    Article  CAS  PubMed  Google Scholar 

  8. Gao S, Wu H, Wang F, Wang Z . Altered differentiation and proliferation of prostate epithelium in mice lacking the androgen receptor cofactor p44/WDR77. Endocrinology 2010; 151: 3941–3953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Peng Y, Chen F, Melamed J, Chiriboga L, Wei J, Kong X et al. Distinct nuclear and cytoplasmic functions of androgen receptor cofactor p44 and association with androgen-independent prostate cancer. Proc Natl Acad Sci USA 2008; 105: 5236–5241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lu J, Qian J, Izvolsky KI, Cardoso WV . Global analysis of genes differentially expressed in branching and non-branching regions of the mouse embryonic lung. Dev Biol 2004; 273: 418–435.

    Article  CAS  PubMed  Google Scholar 

  11. Reymann S, Borlak J . Transcription profiling of lung adenocarcinomas of c-myc-transgenic mice: identification of the c-myc regulatory gene network. BMC Syst Biol 2008; 2: 46.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kuner R, Muley T, Meister M, Ruschhaupt M, Buness A, Xu EC et al. Global gene expression analysis reveals specific patterns of cell junctions in non-small cell lung cancer subtypes. Lung Cancer 2009; 63: 32–38.

    Article  PubMed  Google Scholar 

  13. Wachi S, Yoneda K, Wu R . Interactome-transcriptome analysis reveals the high centrality of genes differentially expressed in lung cancer tissues. Bioinformatics 2005; 21: 4205–4208.

    Article  CAS  PubMed  Google Scholar 

  14. Gemma A, Li C, Sugiyama Y, Matsuda K, Seike Y, Kosaihira S et al. Anticancer drug clustering in lung cancer based on gene expression profiles and sensitivity database. BMC Cancer 2006; 6: 174.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jat PS, Noble MD, Ataliotis P, Tanaka Y, Yannoutsos N, Larsen L et al. Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse. Proc Natl Acad Sci USA 1991; 88: 5096–5100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Langley RR, Ramirez KM, Tsan RZ, Van Arsdall M, Nilsson MB, Fidler IJ . Tissue-specific microvascular endothelial cell lines from H-2K(b)-tsA58 mice for studies of angiogenesis and metastasis. Cancer Res 2003; 63: 2971–2976.

    CAS  PubMed  Google Scholar 

  17. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817–825.

    Article  CAS  PubMed  Google Scholar 

  18. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805–816.

    Article  CAS  PubMed  Google Scholar 

  19. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D . p21 is a universal inhibitor of cyclin kinases. Nature 1993; 366: 701–704.

    Article  CAS  PubMed  Google Scholar 

  20. Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 1994; 78: 59–66.

    Article  CAS  PubMed  Google Scholar 

  21. Dyson N . The regulation of E2F by pRB-family proteins. Genes Dev 1998; 12: 2245–2262.

    Article  CAS  PubMed  Google Scholar 

  22. Templeton DJ, Park SH, Lanier L, Weinberg RA . Nonfunctional mutants of the retinoblastoma protein are characterized by defects in phosphorylation, viral oncoprotein association, and nuclear tethering. Proc Natl Acad Sci USA 1991; 88: 3033–3037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA . Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 1992; 70: 993–1006.

    Article  CAS  PubMed  Google Scholar 

  24. Qin XQ, Chittenden T, Livingston DM, Kaelin WG . Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev 1992; 6: 953–964.

    Article  CAS  PubMed  Google Scholar 

  25. Conlon I, Raff M . Size control in animal development. Cell 1999; 96: 235–244.

    Article  CAS  PubMed  Google Scholar 

  26. Conlon I, Raff M . Control and maintenance of mammalian cell size: response. BMC Cell Biol 2004; 5: 36.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Conlon IJ, Dunn GA, Mudge AW, Raff MC . Extracellular control of cell size. Nat Cell Biol 2001; 3: 918–921.

    Article  CAS  PubMed  Google Scholar 

  28. Sherr CJ, Roberts JM . Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995; 9: 1149–1163.

    Article  CAS  PubMed  Google Scholar 

  29. Andres V, Walsh K . Myogenin expression, cell cycle withdrawal, and phenotypic differentiation are temporally separable events that precede cell fusion upon myogenesis. J Cell Biol 1996; 132: 657–666.

    Article  CAS  PubMed  Google Scholar 

  30. Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ et al. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 1995; 267: 1018–1021.

    Article  CAS  PubMed  Google Scholar 

  31. Skapek SX, Rhee J, Spicer DB, Lassar AB . Inhibition of myogenic differentiation in proliferating myoblasts by cyclin D1-dependent kinase. Science 1995; 267: 1022–1024.

    Article  CAS  PubMed  Google Scholar 

  32. Sherr CJ, McCormick F . The RB and p53 pathways in cancer. Cancer Cell 2002; 2: 103–112.

    Article  CAS  PubMed  Google Scholar 

  33. Chen G, Lee EY . Phenotypic differentiation without permanent cell-cycle arrest by skeletal myocytes with deregulated E2F-1. DNA Cell Biol 1999; 18: 305–314.

    Article  CAS  PubMed  Google Scholar 

  34. Wang J, Helin K, Jin P, Nadal-Ginard B . Inhibition of in vitro myogenic differentiation by cellular transcription factor E2F1. Cell Growth Differ 1995; 6: 1299–1306.

    CAS  PubMed  Google Scholar 

  35. Zhang P, Wong C, DePinho RA, Harper JW, Elledge SJ . Cooperation between the Cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes Dev 1998; 12: 3162–3167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang P, Wong C, Liu D, Finegold M, Harper JW, Elledge SJ . p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step. Genes Dev 1999; 13: 213–224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Classon M, Harlow E . The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2002; 2: 910–917.

    Article  CAS  PubMed  Google Scholar 

  38. Cobrinik D . Pocket proteins and cell cycle control. Oncogene 2005; 24: 2796–2809.

    Article  CAS  PubMed  Google Scholar 

  39. Gonzalo S, Blasco MA . Role of Rb family in the epigenetic definition of chromatin. Cell Cycle 2005; 4: 752–755.

    Article  CAS  PubMed  Google Scholar 

  40. Sherr CJ . Principles of tumor suppression. Cell 2004; 116: 235–246.

    Article  CAS  PubMed  Google Scholar 

  41. Mal A, Chattopadhyay D, Ghosh MK, Poon RY, Hunter T, Harter ML . p21 and retinoblastoma protein control the absence of DNA replication in terminally differentiated muscle cells. J Cell Biol 2000; 149: 281–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sherr CJ . G1 phase progression: cycling on cue. Cell 1994; 79: 551–555.

    Article  CAS  PubMed  Google Scholar 

  43. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 2001; 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  44. Ma W, Wang M, Wang ZQ, Sun L, Graber D, Matthews J et al. Effect of Long-Term Storage in Trizol on Microarray-Based Gene Expression Profiling. Cancer Epidemiol Biomarkers Prev 2010; 19: 2445–2452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc B 1995; 57: 289–300.

    Google Scholar 

  46. Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95: 14863–14868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jakt LM, Cao L, Cheah KS, Smith DK . Assessing clusters and motifs from gene expression data. Genome Res 2001; 11: 112–123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Joe Munch in MD Anderson’s Department of Scientific Publications for editing the manuscript and Shen Gao for performing the experiment as described in Supplementary Figure S1. This work was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant CA16672, National Natural Science Foundation of China (81171922) and Key Project Research Fund of Shaanxi Provincial Science and Technology Program, China (2008K27G01). No additional external funding for this study was received. The funding agency had no role in study design, data collection or analysis, decision to publish, or manuscript preparation.

Author contributions: FZ performed orthotopic injection of cells and bioluminescent imaging. ZG performed the other experiments. ZQW, WM and RED performed DNA microarray analysis. ZW wrote the manuscript.

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Authors and Affiliations

  1. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z Gu, F Zhang & Z Wang

  2. Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China

    Z Gu

  3. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z-Q Wang, W Ma & R E Davis

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  1. Z Gu
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Correspondence to Z Wang.

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Gu, Z., Zhang, F., Wang, ZQ. et al. The p44/wdr77-dependent cellular proliferation process during lung development is reactivated in lung cancer. Oncogene 32, 1888–1900 (2013). https://doi.org/10.1038/onc.2012.207

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