Browse > Article
http://dx.doi.org/10.7314/APJCP.2014.15.9.4101

8-60hIPP5m-Induced G2/M Cell Cycle Arrest Involves Activation of ATM/p53/p21cip1/waf1 Pathways and Delayed Cyclin B1 Nuclear Translocation  

Zeng, Qi-Yan (Department of Biochemistry and Molecular Biology, Guangxi Medical University)
Zeng, Lin-Jie (Department of Orthopaedics, Orthopaedics Hospital)
Huang, Yu (Clinical Laboratory Center, Nanfang Hospital)
Huang, Yong-Qi (Department of Biochemistry and Molecular Biology, Guangxi Medical University)
Zhu, Qi-Fang (Department of Biochemistry and Molecular Biology, Guangxi Medical University)
Liao, Zhi-Hong (Department of Biochemistry and Molecular Biology, Guangxi Medical University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.15, no.9, 2014 , pp. 4101-4107 More about this Journal
Abstract
Protein phosphatase 1 (PP1) is a major serine/threonine phosphatase that controls gene expression and cell cycle progression. The active mutant IPP5 ($8-60hIPP5^m$), the latest member of the inhibitory molecules for PP1, has been shown to inhibit the growth of human cervix carcinoma cells (HeLa). In order to elucidate the underlying mechanisms, the present study assessed overexpression of $8-60hIPP5^m$ in HeLa cells. Flow cytometric and biochemical analyses showed that overexpression of $8-60hIPP5^m$ induced G2/M-phase arrest, which was accompanied by the upregulation of cyclin B1 and phosphorylation of G2/M-phase proteins ATM, p53, $p21^{cip1/waf1}$ and Cdc2, suggesting that $8-60hIPP5^m$ induces G2/M arrest through activation of the ATM/p53/$p21^{cip1/waf1}$/Cdc2/cyclin B1 pathways. We further showed that overexpression of $8-60hIPP5^m$ led to delayed nuclear translocation of cyclin B1. $8-60hIPP5^m$ also could translocate to the nucleus in G2/M phase and interact with $pp1{\alpha}$ and Cdc2 as demonstrated by co-precipitation assay. Taken together, our data demonstrate a novel role for $8-60hIPP5^m$ in regulation of cell cycle in HeLa cells, possibly contributing to the development of new therapeutic strategies for cervix carcinoma.
Keywords
G2/M arrest; HeLa cell; IPP5; nuclear translocation; signal transduction;
Citations & Related Records
Times Cited By KSCI : 6  (Citation Analysis)
연도 인용수 순위
1 Chow JP, Siu WY, Fung TK, et al (2003). DNA damage during the spindle-assembly checkpoint degrades CDC25A, inhibits cyclin-CDC2 complexes, and reverses cells to interphase. Mol Biol Cell, 14, 3989-02.   DOI   ScienceOn
2 Ceulemans H, Bollen M. Functional diversity of protein phosphatas-1, a cellular economizer and reset button. Physiol Rev, 84, 1-39.
3 Cheah PL, Looi LM, Teoh KH, et al (2012). p16(INK4a) is a useful marker of human papillomavirus integration allowing risk stratification for cervical malignancies. Asian Pac J Cancer Prev, 13, 469-72.   과학기술학회마을   DOI   ScienceOn
4 Cheng A, Dean NM, Honkanen RE (2000). Serine/Threonine protein phosphatase type 1$\gamma$1 is required for the completion of cytokinesis in human A549 lung carcinoma cells. J Biol Chem, 275, 1846-54.   DOI   ScienceOn
5 Cohen P.T (2002). Protein phosphatase 1-targeted in many directions. J Cell Sci, 115, 241-56.
6 Dahl J, You J, Benjamin TL (2005). Induction and utilization of an ATM signaling pathway by polyomavirus. J Virol, 79, 13007-17.   DOI   ScienceOn
7 Edelson JR and Brautigan DL (2011). The discodermia calyx toxin calyculin a enhances cyclin d1 phosphorylation and degradation, and arrests cell cycle progression in human breast cancer cells. Toxins (Basel), 3, 105-19.   DOI
8 Grallert A, Chan KY, Alonso-Nunez ML, et al (2012). Removal of centrosomal PP1 by NIMA kinase unlocks the MPF feedback loop to promote mitotic commitment in S. pombe. Curr Biol, 23, 213-22.
9 Honkanen R, Theobald B, Bonness K (2012). A fostriecin sensitive protein phosphatase, serine/threonine protein phosphatase 4 (PP4) is required for faithful chromosome segregation and mitotic progression into anaphase. FASEB J, 26, 839.
10 Andreassen PR, Lacroix FB, Villa-Moruzzi E, et al (1998). Differential subcellular localization of protein phosphatase-1 alpha, gamma1, and delta isoforms during both interphase and mitosis in mammalian cells. J Cell Biol, 141, 1207-15.   DOI
11 Axton JM, Dombradi V, Cohen PT, et al (1990). One of the protein phosphatase 1 isoenzymes in Drosophila is essential for mitosis. Cell, 63, 33-46.   DOI   ScienceOn
12 Wright JH, Munar E, Jameson DR, et al (1999). Mitogen-activated protein kinase kinase activity is required for the G2/M transition of the cell cycle in mammalian fibroblasts. Proc Natl Acad Sci USA, 96, 11335-40.   DOI
13 Bailly E, Pines J, Hunter T, et al (1992). Cytoplasmic accumulation of cyclin B1 in human cells: association with a detergent-resistant compartment and with the centrosome. J Cell Sci, 101, 529-45.
14 Booher R, Beach D (1989). Involvement of a type 1 protein phosphatase encoded by bws1+ in .ssion yeast mitotic control. Cell, 57, 1009-16.   DOI   ScienceOn
15 Boyer SN, Wazer DE, Band V (1996). E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res, 56, 4620-4.
16 Zhou X, Gu Y, Zhang S-L (2012). Association between p53 codon 72 polymorphism and cervical cancer risk among Asians: A huge review and meta-analysis. Asian Pac J Cancer Prev, 13, 4909-14.   과학기술학회마을   DOI   ScienceOn
17 Theobald B, Bonness K, Musiyenko A, et al (2013). Suppression of Ser/Thr phosphatase 4 (PP4C/PPP4C) mimics a novel post-mitotic action of fostriecin, producing mitotic slippage followed by tetraploid cell death. Mol Cancer Res, 11, 845-55.   DOI
18 Verma AK and Prasad SB (2012). Bioactive component, cantharidin from mylabris cichorii and its antitumor activity against Ehrlich ascites carcinoma. Cell Biol Toxicol, 28, 133-47.   DOI
19 Wang XJ, Liu B, Li N, et al (2008). IPP5, A novel protein inhibitor of protein phosphatase 1, promotes G1/S progression in a thr-40-dependent manner. J Biol Chem, 283, 12076-84.   DOI
20 Woodworth CD, Doniger J, DiPaolo JA (1989). Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical carcinoma. J Virol, 63, 159-64.
21 Xia H, Qi H, Li Y, et al (2002). LATS1 tumor suppressor regulates G2/M transition and apoptosis. Oncogene, 21, 1233-41.   DOI
22 Zeng QY, Huang Y, Zeng LJ, et al (2012). IPP5, a Novel Inhibitor of Protein Phosphatase 1, Suppresses Tumor Growth and Progression of Cervical Carcinoma Cells by Inducing G2/M Arrest. Cancer Genetics, 205, 442-52.   DOI
23 Zhang E-Y, Tang X-D (2012). Human papillomavirus type 16/18 oncoproteins: potential therapeutic targets in non-smoking associated lung cancer. Asian Pac J Cancer Prev, 13, 5363-9.   과학기술학회마을   DOI   ScienceOn
24 Zhao X, Madden-Fuentes RJ, Lou BX, et al (2008). Ataxia telangiectasia-mutated damage-signaling kinase- and proteasome-dependent destruction of Mre11-Rad50-Nbs1 subunits in Simian virus 40-infected primate cells. J Virol, 82, 5316-28.   DOI
25 Roberts EC, Shapiro PS, Nahreini TS, et al (2002). Distinct cell cycle timing requirements for extracellular signal-regulated kinase and phosphoinositide 3-kinase signaling pathways in somatic cell mitosis. Mol Cell Biol, 22, 7226-41.   DOI
26 Pines J, Hunter T (1991). Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. J Cell Biol, 115, 1-17.   DOI
27 Poggioli GJ, Dermody TS, Tyler KL (2001). Reovirus-induced $\sigma$1s-dependent G2/M phase cell cycle arrest is associated with inhibition of p34cdc2. J Virol, 75, 7429-34.   DOI
28 Shirata N, Kudoh A, Daikoku T, et al (2005). Activation of ataxia telangiectasia-mutated DNA damage checkpoint signal transduction elicited by herpes simplex virus infection. J Biol Chem, 280, 30336-41.   DOI
29 Raub SHA, Isa NM, Zailani HA, et al (2014). Distribution of HPV genotypes in cervical cancer in multi-ethnic Malaysia. Asian Pac J Cancer Prev, 15, 651-6.   과학기술학회마을   DOI   ScienceOn
30 Rubiolo JA, Lopez-Alonso H, Vega FV, et al (2012). Comparative study of toxicological and cell cycle effects of okadaic acid and dinophysistoxin-2 in primary rat hepatocytes. Life Sci, 90, 416-23.   DOI
31 Sogawa K, Yamada T, Sugita A, et al (1996). Role of protein phosphatase in malignant osteogenic and soft tissue tumors. Res Commun Mol Pathol Pharmacol, 93, 33-42
32 Subramanian N, Chinnappan S (2013). Prediction of promiscuous epitopes in the E6 protein of three high risk human papilloma viruses: a computational approach. Asian Pac J Cancer Prev, 14, 4167-75.   과학기술학회마을   DOI   ScienceOn
33 Tang J, Agrawal T, Cheng Q, et al (2013). Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation. PLoS One, 8, 55813.   DOI
34 Lu ZX, Wan GH, Guo HR, et al (2013). Protein phosphatase 1 inhibits p53 signaling by dephosphorylating and stabilizing Mdmx. Cell Signal, 25, 796-804.   DOI
35 Kinoshita N, Ohkura H, Yanagida M (1990). Distinct, essential roles of type 1 and 2A rotein phosphatases in the control of the fission yeast cell division cycle. Cell, 63, 405-15.   DOI
36 Nimmo GA, Cohen P (1978). The regulation of glycogen metabolism. Purification and characterisation of protein phosphatase inhibitor-1 from rabbit skeletal muscle. Eur J Biochem, 87, 341-51.   DOI
37 Lavin MF, Kozlov S (2007). ATM activation and DNA damage response. Cell Cycle, 6, 931-42.   DOI
38 Luo MH, Rosenke K, Czornak K, et al (2007). Human cytomegalovirus disrupts both ataxia telangiectasia mutated protein (ATM)- and ATM-Rad3-related kinase-mediated DNA damage responses during lytic infection. J Virol, 81, 1934-50.   DOI
39 Mumby MC, Walter G (1993). Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth. Physiol Rev, 73, 673-99.   DOI
40 Nurse P (1990). Universal control mechanism regulating onset of M-phase. Nature, 344, 503-8.   DOI   ScienceOn
41 Ohkura H, Kinoshita N, Miyatani S, et al (1989). The .ssion yeast dis2+ gene required for chromosome disjoining encodes one of two putative type 1 protein phosphatases. Cell, 57, 997-07.   DOI
42 Paulson JR, Patzlaff JS, Vallis AJ (1996). Evidence that the endogenous histone H1 phosphatase in HeLa mitotic chromosomes is protein phosphatase 1, not protein phosphatase 2A. J Cell Sci, 109, 1437-47.
43 Li J, Huang R, Schmidt JE, et al (2013). Epidemiological features of human papillomavirus (HPV) Infection among women living in mainland China. Asian Pac J Cancer Prev, 14, 4015-23   과학기술학회마을   DOI
44 Dash BC, El-Deiry WSP (2005). Phosphorylation of $p21^{cip1/waf1}$ in G2/M promotes cyclin B-Cdc2 kinase activity. Mol Cell Biol, 25, 3364-87.   DOI   ScienceOn