Abstract
CDK11p58, a G2/M-specific protein kinase, has been shown to be associated with apoptosis in many cell lines, with largely unknown mechanisms. Our previous study proved that CDK11p58-enhanced cycloheximide (CHX)-induced apoptosis in SMMC-7721 hepatocarcinoma cells. Here we report for the first time that ectopic expression of CDK11p58 down-regulates Bcl-2 expression and its Ser70, Ser87 phosphorylation in CHX-induced apoptosis in SMMC-7721 cells. Overexpression of Bcl-2 counteracts the pro-apoptotic activity of CDK11p58. Furthermore, we confirm that the kinase activity of CDK11p58 is essential to the down-regulation of Bcl-2 as well as apoptosis. Taken together, these results demonstrate that CDK11p58 down-regulates Bcl-2 in pro-apoptosis pathway depending on its kinase activity, which elicits survival signal in hepatocarcinoma cells.
Similar content being viewed by others
References
Ellis RE, Yuan JY, Horvitz HR (1991) Mechanisms and functions of cell death. Annu Rev Cell Biol 7:663–698
Williams GT, Smith CA (1993) Molecular regulation of apoptosis: genetic controls on cell death. Cell 74:777–779
Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308
Evan G, Littlewood T (1998) A matter of life and cell death. Science 281:1317–1322
Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326
Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619
Li P, Nijhawan D, Budihardjo I et al (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489
Zou H, Henzel WJ, Liu X et al (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90:405–413
Breitschopf K, Haendeler J, Malchow P et al (2000) Prottranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: molecular characterization of the involved signaling pathway. Mol Cell Biol 20:1886–1896
Ito T, Deng X, Carr B et al (1997) Bcl-2 phosphorylation required for anti-apoptosis function. J Biol Chem 272:11671–11673
Weil M, Jacobson MD, Coles HS et al (1996) Constitutive expression of the machinery for programmed cell death. J Cell Biol 133:1053–1059
Shi L, Nishioka WK, Th’ng J et al (1994) Premature p34cdc2 activation required for apoptosis. Science 263:1143–1145
Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81:323–330
Lahti JM, Xiang J, Heath LS et al (1995) PITSLRE protein kinase activity is associated with apoptosis. Mol Cell Biol 15:1–11
Cai MM, Zhang SW, Zhang S et al (2002) Different effects of p58PITSLRE on the apoptosis induced by etoposide, cycloheximide and serum-withdrawal in human hepatocarcinoma cells. Mol Cell Biochem 238:49–55
Zhang S, Cai M, Zhang S et al (2002) Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3. J Biol Chem 277:35314–35322
Tan KO, Tan KM, Chan SL et al (2001) MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with Bax through its Bcl-2 homology domains. J Biol Chem 276:2802–2807
Li Z, Wang H, Zong H et al (2005) Downregulation of beta1,4-galactosyltransferase 1 inhibits CDK11(p58)-mediated apoptosis induced by cycloheximide. Biochem Biophys Res Commun 327:628–636
Yin XM, Oltvai ZN, Korsmeyer SJ (1994) BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369:321–323
Tschopp J, Thome M, Hofmann K et al (1998) The fight of viruses against apoptosis. Curr Opin Genet Dev 8:82–87
Yang E, Zha J, Jockel J et al (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291
Sawada M, Nakashima S, Banno Y et al (2006) Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptosis pathway in glioma cells. Oncogene 25:7440
Armstrong RC, Aja T, Xiang J et al (1996) Fas-induced activation of the cell death-related protease CPP32 Is inhibited by Bcl-2 and by ICE family protease inhibitors. J Biol Chem 271:16850–16855
Lamothe B, Aggarwal BB (2002) Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppression of caspases-8, 7, and 3 and BID cleavage in human acute myelogenous leukemia cell line HL-60. J Interferon Cytokine Res 22:269–279
Cornelis S, Bruynooghe Y, Denecker G et al (2000) Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. Mol Cell 5:597–605
Xiang J, Lahti JM, Grenet J et al (1994) Molecular cloning and expression of alternatively spliced PITSLRE protein kinase isoforms. J Biol Chem 269:15786–15794
Zong H, Li Z, Liu L et al (2005) Cyclin-dependent kinase 11(p58) interacts with HBO1 and enhances its histone acetyltransferase activity. FEBS Lett 579:3579–3588
Hockenbery D, Nunez G, Milliman C et al (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336
Zhu W, Cowie A, Wasfy GW et al (1996) Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types. Embo J 15:4130–4141
Jin Z, May WS, Gao F et al (2006) Bcl2 suppresses DNA repair by enhancing c-Myc transcriptional activity. J Biol Chem 281:14446–14456
Beyaert R, Kidd VJ, Cornelis S et al (1997) Cleavage of PITSLRE kinases by ICE/CASP-1 and CPP32/CASP-3 during apoptosis induced by tumor necrosis factor. J Biol Chem 272:11694–11697
Chen C, Yan J, Sun Q et al (2006) Induction of apoptosis by p110C requires mitochondrial translocation of the proapoptotic BCL-2 family member BAD. FEBS Lett 580:813–821
Thomas A, Giesler T, White E (2000) p53 mediates bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway. Oncogene 19:5259–5269
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yun, X., Wu, Y., Yao, L. et al. CDK11p58 protein kinase activity is associated with Bcl-2 down-regulation in pro-apoptosis pathway. Mol Cell Biochem 304, 213–218 (2007). https://doi.org/10.1007/s11010-007-9502-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-007-9502-x