Phospho‑regulation of Cdc14A by polo‑like kinase 1 is involved in β‑cell function and cell cycle regulation

Hu,Haiying; Shao,Dandan; Wang,Leilei; He,Fang; Huang,Xiaoxu; Lu,Yanyu; Xiang,Xiaona; Zhu,Susu; Zhang,Pianhong; Li,Jianru; Chen,Jingsen

doi:10.3892/mmr.2019.10653

Phospho‑regulation of Cdc14A by polo‑like kinase 1 is involved in β‑cell function and cell cycle regulation

Authors:
- Haiying Hu
- Dandan Shao
- Leilei Wang
- Fang He
- Xiaoxu Huang
- Yanyu Lu
- Xiaona Xiang
- Susu Zhu
- Pianhong Zhang
- Jianru Li
- Jingsen Chen
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Affiliations: Department of Clinical Nutrition, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China, Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
Published online on: September 9, 2019 https://doi.org/10.3892/mmr.2019.10653
Pages: 4277-4284

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Abstract

The objective of the present study was to investigate the effects of polo‑like kinase 1 (PLK1) and the phosphorylation of human cell division cycle protein 14A (Cdc14A) by PLK1 on β‑cell function and cell cycle regulation. Mouse β‑TC3 cells were incubated with small interfering RNA (siRNA) to knock down the expression of PLK1. Cell cycle analysis was performed using flow cytometry, and cell proliferation and apoptosis was determined. Insulin secretion was evaluated by a radioimmunoassay under both low and high glucose conditions. Mouse β‑TC3 cells were transfected with a wild type or a non‑phosphorylatable Cdc14A mutant (Cdc14AS351A/363A; Cdc14AAA) to investigate whether the phosphorylation of Cdc14A is involved in cellular regulation of PLK1 under high glucose conditions. It was found that PLK1 siRNA significantly promoted cellular apoptosis, inhibited cell proliferation, decreased insulin secretion and reduced Cdc14A expression under both low and high glucose conditions. Cdc14A overexpression promoted β‑TC3 cell proliferation and insulin secretion, while Cdc14AAA overexpression inhibited cell proliferation and insulin secretion under high glucose conditions. PLK1 siRNA partially reversed the proliferation‑promoting effects of Cdc14A and further intensified the inhibition of proliferation by Cdc14AAA under high glucose conditions. Similarly, Cdc14A overexpression partially reversed the insulin‑inhibiting effects of PLK1 siRNA, while Cdc14AAA overexpression showed a synergistic inhibitory effect on insulin secretion with PLK1 siRNA under high glucose conditions. In conclusion, PLK1 promoted cell proliferation and insulin secretion while inhibiting cellular apoptosis in β‑TC3 cell lines under both low and high glucose conditions. In addition, the phospho‑regulation of Cdc14A by PLK1 may be involved in β‑TC3 cell cycle regulation and insulin secretion under high glucose conditions.

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1	Deng S, Vatamaniuk M, Huang X, Doliba N, Lian MM, Frank A, Velidedeoglu E, Desai NM, Koeberlein B, Wolf B, et al: Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes. 53:624–632. 2004. View Article : Google Scholar : PubMed/NCBI
2	Prentki M and Nolan CJ: Islet beta cell failure in type 2 diabetes. J Clin Invest. 116:1802–1812. 2006. View Article : Google Scholar : PubMed/NCBI
3	Nyblom HK, Bugliani M, Fung E, Boggi U, Zubarev R, Marchetti P and Bergsten P: Apoptotic, regenerative, and immune-related signaling in human islets from type 2 diabetes individuals. J Proteome Res. 8:5650–5656. 2009. View Article : Google Scholar : PubMed/NCBI
4	Misfeldt A, Costa RH and Gannon M: Beta-cell proliferation, but not neogenesis, following 60% partial pancreatectomy is impaired in the absence of FoxM1. Diabetes. 57:3069–3077. 2008. View Article : Google Scholar : PubMed/NCBI
5	Barr FA, Silljé HH and Nigg EA: Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol. 5:429–440. 2004. View Article : Google Scholar : PubMed/NCBI
6	Zitouni S, Nabais C, Jana SC, Guerrero A and Bettencourt-Dias M: Bettencourt-Dias M. Polo-like kinases: Structural variations lead to multiple functions. Nat Rev Mol Cell Biol. 15:433–452. 2014. View Article : Google Scholar : PubMed/NCBI
7	Bruinsma W, Raaijmakers JA and Medema RH: Switching Polo-like kinase-1 on and off in time and space. Trends Biochem Sci. 37:534–542. 2012. View Article : Google Scholar : PubMed/NCBI
8	Petronczki M, Lénárt P and Peters JM: Polo on the rise from mitotic entry to cytokinesis with Plk1. Dev Cell. 14:646–659. 2008. View Article : Google Scholar : PubMed/NCBI
9	Liu X and Erikson RL: Activation of Cdc2/cyclin B and inhibition of centrosome amplification in cells depleted of Plk1 by siRNA. Proc Natl Acad Sci USA. 99:8672–8676. 2002. View Article : Google Scholar : PubMed/NCBI
10	Lénárt P, Petronczki M, Steegmaier M, Di Fiore B, Lipp JJ, Hoffmann M, Rettig WJ, Kraut N and Peters JM: The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol. 17:304–315. 2007. View Article : Google Scholar : PubMed/NCBI
11	de Cárcer G, Manning G and Malumbres M: From Plk1 to Plk5: Functional evolution of polo-like kinases. Cell Cycle. 10:2255–2262. 2011. View Article : Google Scholar : PubMed/NCBI
12	Strebhardt K and Ullrich A: Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer. 6:321–330. 2006. View Article : Google Scholar : PubMed/NCBI
13	Eckerdt F, Yuan J and Strebhardt K: Polo-like kinases and oncogenesis. Oncogene. 24:267–276. 2005. View Article : Google Scholar : PubMed/NCBI
14	Bassermann F, Frescas D, Guardavaccaro D, Busino L, Peschiaroli A and Pagano M: The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell. 134:256–267. 2008. View Article : Google Scholar : PubMed/NCBI
15	Mocciaro A, Berdougo E, Zeng K, Black E, Vagnarelli P, Earnshaw W, Gillespie D, Jallepalli P and Schiebel E: Vertebrate cells genetically deficient for Cdc14A or Cdc14B retain DNA damage checkpoint proficiency but are impaired in DNA repair. J Cell Biol. 189:631–639. 2010. View Article : Google Scholar : PubMed/NCBI
16	Mocciaro A and Schiebel E: Cdc14: A highly conserved family of phosphatases with non-conserved functions? J Cell Sci. 123:2867–2876. 2010. View Article : Google Scholar : PubMed/NCBI
17	Chen NP, Uddin B, Voit R and Schiebel E: Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion. Proc Natl Acad Sci USA. 113:990–995. 2016. View Article : Google Scholar : PubMed/NCBI
18	Yuan K, Hu H, Guo Z, Fu G, Shaw AP, Hu R and Yao X: Phospho-regulation of HsCdc14A By Polo-like kinase 1 is essential for mitotic progression. J Biol Chem. 282:27414–27423. 2007. View Article : Google Scholar : PubMed/NCBI
19	Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, et al: International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 355:1318–1330. 2006. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Hanley NA, Hanley KP, Miettinen PJ and Otonkoski T: Weighing up beta-cell mass in mice and humans: Self-renewal, progenitors or stem cells? Mol Cell Endocrinol. 288:79–85. 2008. View Article : Google Scholar : PubMed/NCBI
22	Xu X, D'Hoker J, Stangé G, Bonné S, De Leu N, Xiao X, Van de Casteele M, Mellitzer G, Ling Z, Pipeleers D, et al: Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 132:197–207. 2008. View Article : Google Scholar : PubMed/NCBI
23	Rieck S, Zhang J, Li Z, Liu C, Naji A, Takane KK, Fiaschi-Taesch NM, Stewart AF, Kushner JA and Kaestner KH: Overexpression of hepatocyte nuclear factor-4α initiates cell cycle entry, but is not sufficient to promote β-cell expansion in human islets. Mol Endocrinol. 26:1590–1602. 2012. View Article : Google Scholar : PubMed/NCBI
24	Sharma A, Yerra VG and Kumar A: Emerging role of Hippo signalling in pancreatic biology: YAP re-expression and plausible link to islet cell apoptosis and replication. Biochimie. 133:56–65. 2017. View Article : Google Scholar : PubMed/NCBI
25	García-Ocaña A, Vasavada RC, Takane KK, Cebrian A, Lopez-Talavera JC and Stewart AF: Using beta-cell growth factors to enhance human pancreatic Islet transplantation. J Clin Endocrinol Metab. 86:984–988. 2001. View Article : Google Scholar : PubMed/NCBI
26	Montaña E, Bonner-Weir S and Weir GC: Transplanted beta cell response to increased metabolic demand. Changes in beta cell replication and mass. J Clin Invest. 93:1577–1582. 1994. View Article : Google Scholar : PubMed/NCBI
27	Vasavada RC, Gonzalez-Pertusa J, Fujinaka Y, Fiaschi-Taesch N, Cozar-Castellano I and Garcia-Ocaña A: Growth factors and beta cell replication. Int J Biochem Cell Biol. 38:931–950. 2006. View Article : Google Scholar : PubMed/NCBI
28	Lowell BB and Shulman GI: Mitochondrial dysfunction and type 2 diabetes. Science. 307:384–387. 2005. View Article : Google Scholar : PubMed/NCBI
29	Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA and Donath MY: Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 110:851–860. 2002. View Article : Google Scholar : PubMed/NCBI