Annals of Pediatric Endocrinology and Metabolism

Korean Society of Pediatric Endocrinology (대한소아내분비학회)
권호 표지
DOI QR코드

DOI QR Code

The role of p21/CIP1/WAF1 (p21) in the negative regulation of the growth hormone/growth hormone receptor and epidermal growth factor/epidermal growth factor receptor pathways, in growth hormone transduction defect

  • Kostopoulou, Eirini (Paediatric Endocrine Research Laboratory, Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, University of Patras School of Medicine) ;
  • Gil, Andrea Paola Rojas (Faculty of Human Movement and Quality of Life Sciences, Department of Nursing, University of Peloponnese) ;
  • Spiliotis, Bessie E. (Paediatric Endocrine Research Laboratory, Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, University of Patras School of Medicine)
  • Received : 2018.03.18
  • Accepted : 2018.10.17
  • Published : 2018.12.30
⟨ Previous Next ⟩

Abstract

Purpose: Growth hormone transduction defect (GHTD) is characterized by severe short stature, impaired STAT3 (signal transducer and activator of transcription-3) phosphorylation and overexpression of the cytokine inducible SH2 containing protein (CIS) and p21/CIP1/WAF1. To investigate the role of p21/CIP1/WAF1 in the negative regulation of the growth hormone (GH)/GH receptor and Epidermal Growth Factor (EGF)/EGF Receptor pathways in GHTD. Methods: Fibroblast cultures were developed from gingival biopsies of 1 GHTD patient and 1 control. The protein expression and the cellular localization of p21/CIP1/WAF1 was studied by Western immunoblotting and immunofluorescence, respectively: at the basal state and after induction with $200-{\mu}g/L$ human GH (hGH) (GH200), either with or without siRNA CIS (siCIS); at the basal state and after inductions with $200-{\mu}g/L$ hGH (GH200), $1,000-{\mu}g/L$ hGH (GH1000) or 50-ng/mL EGF. Results: After GH200/siCIS, the protein expression and nuclear localization of p21 were reduced in the patient. After successful induction of GH signaling (control, GH200; patient, GH1000), the protein expression and nuclear localization of p21 were reduced. After induction with EGF, p21 translocated to the cytoplasm in the control, whereas in the GHTD patient it remained located in the nucleus. Conclusion: In the GHTD fibroblasts, when CIS is reduced, either after siCIS or after a higher dose of hGH (GH1000), p21's antiproliferative effect (nuclear localization) is also reduced and GH signaling is activated. There also appears to be a positive relationship between the 2 inhibitors of GH signaling, CIS and p21. Finally, in GHTD, p21 seems to participate in the regulation of both the GH and EGF/EGFR pathways, depending upon its cellular location.

Keywords

References

  1. Rojas-Gil AP, Ziros PG, Diaz L, Kletsas D, Basdra EK, Alexandrides TK, et al. Growth hormone/JAK-STAT axis signal-transduction defect. A novel treatable cause of growth failure. FEBS J 2006;273:3454-66. https://doi.org/10.1111/j.1742-4658.2006.05347.x
  2. Gil AP, Kostopoulou E, Karageorgou I, Kamzelas K, Spiliotis BE. Increased growth hormone receptor (GHR) degradation due to over-expression of cytokine inducible SH2 domain-containing protein (CIS) as a cause of GH transduction defect (GHTD). J Pediatr Endocrinol Metab 2012;25:897-908.
  3. Kostopoulou E, Rojas-Gil AP, Karvela A, Spiliotis BE. Epidermal growth factor receptor (EGFR) involvement in successful growth hormone (GH) signaling in GH transduction defect. J Pediatr Endocrinol Metab 2017;30:221-30.
  4. Lee MH, Reynisdottir I, Massague J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 1995;9:639-49. https://doi.org/10.1101/gad.9.6.639
  5. Luo Y, Hurwitz J, Massague J. Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature 1995;375:159-61. https://doi.org/10.1038/375159a0
  6. Barboza JA, Liu G, Ju Z, El-Naggar AK, Lozano G. p21 delays tumor onset by preservation of chromosomal stability. Proc Natl Acad Sci U S A 2006;103:19842-7. https://doi.org/10.1073/pnas.0606343104
  7. Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 2009;9:400-14. https://doi.org/10.1038/nrc2657
  8. Cmielova J, Rezacova M. p21Cip1/Waf1 protein and its function based on a subcellular localization corrected. J Cell Biochem 2011;112:3502-6. https://doi.org/10.1002/jcb.23296
  9. Winters ZE, Leek RD, Bradburn MJ, Norbury CJ, Harris AL. Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis. Breast Cancer Res 2003;5:R242-9. https://doi.org/10.1186/bcr654
  10. Suzuki A, Tsutomi Y, Akahane K, Araki T, Miura M. Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. Oncogene 1998;17:931-9. https://doi.org/10.1038/sj.onc.1202021
  11. Coqueret O, Gascan H. Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1. J Biol Chem 2000;275:18794-800. https://doi.org/10.1074/jbc.M001601200
  12. Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 2004;14:501-13. https://doi.org/10.1016/S1097-2765(04)00256-4
  13. Hussain T, Saha D, Purohit G, Kar A, Kishore Mukherjee A, Sharma S, et al. Transcription regulation of CDKN1A (p21/CIP1/WAF1) by TRF2 is epigenetically controlled through the REST repressor complex. Sci Rep 2017;7:11541. https://doi.org/10.1038/s41598-017-11177-1
  14. Her J, Jeong YY, Chung IK. PIAS1-mediated sumoylation promotes STUbL-dependent proteasomal degradation of the human telomeric protein TRF2. FEBS Lett 2015;589:3277-86. https://doi.org/10.1016/j.febslet.2015.09.030
  15. Hodjat M, Haller H, Dumler I, Kiyan Y. Urokinase receptor mediates doxorubicin-induced vascular smooth muscle cell senescence via proteasomal degradation of TRF2. J Vasc Res 2013;50:109-23. https://doi.org/10.1159/000343000
  16. Kim W, Ludlow AT, Min J, Robin JD, Stadler G, Mender I, et al. Regulation of the human telomerase gene TERT by telomere position effect-over long distances (TPEOLD): implications for aging and cancer. PLoS Biol 2016;14:e2000016. https://doi.org/10.1371/journal.pbio.2000016
  17. Augustine T, Maitra R, Goel S. Telomere length regulation through epidermal growth factor receptor signaling in cancer. Genes Cancer 2017;8:550-8.
  18. Sheng G, Bernabe KQ, Guo J, Warner BW. Epidermal growth factor receptor-mediated proliferation of enterocytes requires p21waf1/cip1 expression. Gastroenterology 2006;131:153-64. https://doi.org/10.1053/j.gastro.2006.05.007
  19. Heeg S, Hirt N, Queisser A, Schmieg H, Thaler M, Kunert H, et al. EGFR overexpression induces activation of telomerase via PI3K/AKT-mediated phosphorylation and transcriptional regulation through Hif1-alpha in a cellular model of oral-esophageal carcinogenesis. Cancer Sci 2011;102:351-60. https://doi.org/10.1111/j.1349-7006.2010.01796.x
  20. Tonko-Geymayer S, Goupille O, Tonko M, Soratroi C, Yoshimura A, Streuli C, et al. Regulation and function of the cytokine-inducible SH-2 domain proteins, CIS and SOCS3, in mammary epithelial cells. Mol Endocrinol 2002;16:1680-95. https://doi.org/10.1210/mend.16.7.0872