Abstract
The role of p38α stress-kinase in the regulation of the premature senescence program induced by the histone deacetylase inhibitor sodium butyrate (NaB) was studied in rodent transformed cell lines. The study was carried out on E1A+cHa-ras transformants obtained from mouse embryonic fibroblasts null for the Mapk14 gene encoding p38α stress-kinase (the mERasp38−/− cell line), or for the PPM1D gene encoding the Wip1 phosphatase (the mERas Wip1−/− cell line), whose absence led to constitutive activation of p38α kinase. It was found that after NaB treatment both cell lines completely stopped proliferation due to irreversible G1/S cell cycle arrest. In both lines a marker of senescence appeared—the activity of β-galactosidase (SA-β-Gal). As well, treatment of the cells with NaB for several days led to morphological cell changes, such as partial readjustment of the actin cytoskeleton, spreading on the substrate, and heterochromatin focus formation (SAHF) in the senescent cell nuclei. These data allow us to suggest that, in the absence of functionally active p38α kinase, the NaB-induced irreversible process of cellular senescence may occur via alternative pathways for downregulation of the cell cycle.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- NaB:
-
sodium butyrate
- SA-β-Gal:
-
senescence-associated β-galactosidase
- MAP-kinase:
-
mitogen-activated protein kinase
- BSA:
-
bovine serum albumin
References
Are, A.F., Galkin, V.E., Pospelova, T.V., and Pinaev, G.P., The p65/Re1A Subunit of NF-kB Interacts with Actin-containing Structures, Exp. Cell Res., 2000, vol. 256, pp. 533–544.
Besson, A., Assoian, R.K., and Roberts, J.M., Regulation of the Cytoskeleton: an Oncogenic Function for CDK Inhibitors? Nat. Rev. Cancer, 2004, vol. 4, pp. 948–955.
Bodnar, A.G., Ouellette, M., Frolkis, M., Holt, S.E., Chiu, C.P., Morin, G.B., Harley, C.B., Shay, J.W., Lichtsteiner, S., and Wright, W.E., Extension of Life-span by Introduction of Telomerase into Normal Human Cells, Science, 1998, vol. 279, pp. 349–352.
Bulavin, D.V., Higashimoto, Y., Popoff, I.J., Gaarde, W.A., Basrur, V., Potapova, O., Appella, E., and Fornace, A.J., Initiation of a G2/M Checkpoint after Ultraviolet Radiation Requires p38 Kinase, Nature, 2001, vol. 411, pp. 102–107.
Bulavin, D.V., Pospelov, V.A., and Pospelova, T.V., Oncoproteins E1Aad5 Interact with Universal Inhibitor of Cyclin-dependent Kinases p21/waf-1 and Inhibit its Activity in E1A+cHa-ras Transformants, Molek. Biol., 1999a, vol. 33, no. 4, pp. 641–643.
Bulavin, D.V., Saito, S., Hollander, M.C., Sakaguchi, K., Anderson, C.W., Appella, E., and Fornace, A.J., Phosphorylation of Human p53 by p38 Kinase Coordinates N-Terminal Phosphorylation and Apoptosis in Response to UV Radiation, EMBO J., 1999b, vol. 18, pp. 6845–6854.
Deng, Q., Liao, R., Wu, B.-L., and Sun, P., High-intensity ras Signaling Induces Premature Senescence by Activating p38 Pathway in Primary Human Fibroblasts, J. Biol. Chem., 2004, vol. 279, pp. 1050–1059.
Dimri, G.P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E.E., Linskens, M., Rubelj, I., Pereira-Smith, O., Peacocke, M., and Campisi, J., A Biomarker That Identifies Senescent Human Cells in Culture and in Aging Skin in vivo, Proc. Natl. Acad. Sci. USA, 1995, vol. 92, pp. 9363–9367.
Goodwin, E.C., Yang, E., Lee, C.J., Lee, H.W., DiMaio, D., and Hwang, E.S., Rapid Induction of Senescence in Human Cervical Carcinoma Cells, Proc. Natl. Acad. Sci. USA, 2000, vol. 97, pp. 10978–10983.
Gourlay, C.W. and Ayscough, K.R., The Actin Cytoskeleton: a Key Regulator of Apoptosis and Ageing? Nature Rev. Mol. Cell Biol., 2005, vol. 6, pp. 583–589.
Hayflick, L., The Limited in vitro Lifetime of Human Diploid Cell Strains, Exp. Cell Res., 1965, vol. 37, pp. 614–636.
Ishikawa, F., Cellular Senescence, an Unpopular yet Trustworthy Tumor Suppressor Mechanism, Cancer Sci., 2003, vol. 94, pp. 944–947.
Iwasa, H., Han, J., and Ishikawa, F., Mitogen-activated Protein Kinase p38 Defines the Common Senescence-signalling Pathway, Genes Cells., 2003, vol. 38, pp. 131–144.
Jung, J.-W., Cho, S.-D., Ahn, N.-S., Yang, S.-R., Park, J.-S., Jo, E.-H., Hwang, J.-W., Jung, J.-Y., Kim, S.-H., Kang, K.-S., and Lee, Y.-S., Ras/MAP Kinase Pathways are Involved in RAS Specific Apoptosis Induced by Sodium Butyrate, Cancer Lett., 2005, vol. 225, pp. 199–206.
Kang, S., Jung, M., Kim, C.-W., and Shin, D.Y., Inactivation of p38 Kinase Delays the Onset of Senescence in Rabbit Articular Chondrocytes, Mech. Ageing Dev., 2005, vol. 126, pp. 591–597.
Mathon, N.F. and Lloyd, A.C., Cell Senescence and Cancer, Nature Rev. Cancer, 2001, vol. 1, pp. 203–213.
Mikhailov, A., Shinora, M., and Rieder, C.L., Topoisomerase II and Histone Deacetylase Inhibitors Delay the G2/M Transition by Triggering the p38 MAPK Checkpoint Pathway, J. Cell Biol., 2004, vol. 166, pp. 517–526.
Minden, A., Lin, A., Claret, F.X., Abo, A., and Karin, M., Selective Activation of the JNK Signaling Cascade and c-Jun Transcriptional Activity by the Small GTPases Rac and Cdc42Hs, Cell, 1995, vol. 81, pp. 1147–1157.
Narita, M., Nunez, S., Heard, E., Narita, M., Lin, A.W., Hearn, S.A., Spector, D.L., Hannon, G.J., and Lowe, S.W., Rb-mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence, Cell, 2003, vol. 113, pp. 703–716.
Ohtani, N., Yamakoshi, K., Takahashi, A., and Hara, E., The p16/Ink4a-Rb Pathway: Molecular Link between Cellular Senescence and Tumor Suppression, J. Med. Invest., 2004, vol. 51, pp. 146–153.
Ridley, A.J., Allen, W.E., Peppelenbosch, M., and Jones, G.E., Rho Family Proteins and Cell Migration, Biochem. Soc. Symp., 1999, vol. 65, pp. 111–123.
Roninson, I.B., Tumor Cell Senescence in Cancer Treatment, Cancer Res., 2003, vol. 63, pp. 2705–2715.
Sherr, C.J. and DePinho, R.A., Cellular Senescence: Mitotic Clock or Culture Shock? Cell, 2000, vol. 102, pp. 407–410.
Takenaka, K., Moriguchi, T., and Nishida, E., Activation of the Protein kinase p38 in the Spindle Assembly Checkpoint and Mitotic Arrest, Science, 1998, vol. 280, pp. 599–602.
Terao, Y., Nishida, J., Horiuchi, S., Rong, F., Ueoka, Y., Matsuda, T., Kato, H., Furugenxxx Y., Yoshida, K., Kato, K., and Wake, N., Sodium Butyrate Induces Growth Arrest and Senescence-like Phenotypes in Gynecologic Cancer Cells, Int. J. Cancer, 2001, vol. 94, pp. 257–267.
Timofeev, O., Lee, T.,Yi., and Bulavin, D.V., A Subtle Change in p38 MAPK Activity is Sufficient to Suppress in vivo Tumorigenesis, Cell Cycle, 2005, vol. 4, pp. 118–120.
Toussaint, O., Dumont, P., Dierick, J.F., Pascal, T., Frippiat, C., Chainiaux, F., Sluse, F., Eliaers, F., and Remacle, J., Stress-induced Premature Senescence. Essence of Life, Evolution, Stress and Aging, Ann. N.Y. Acad. Sci., 2000, vol. 908, pp. 85–98.
Wang, W., Chen, J.X., Liao, R., Deng, Q., Zhou, J.J., Huang, S., and Sun, P., Sequential Activation of the MEK-extracellular Signal-activated Kinase and MKK3/6-p38 Mitogen-activated Protein Kinase Pathways Mediates Oncogenic ras-Induced Premature Senescence, Mol. Cell. Biol., 2002, vol. 22, pp. 3389–3403.
Wei, S. and Sedivy, J.M., Expression of Catalytically Active Telomerase Does not Prevent Premature Senescence Caused by Overexpression of Oncogenic Ha-Ras in Normal Human Fibroblasts, Cancer Res., 1999, vol. 59, pp. 1539–1543.
Zhang, L., Deng, M., Parthasarathy, R., Wang, L., Mongan, M., Molkentin, J.D., Zheng, Yi., and Xia, Y., MEKK1 Transduces Activin Signals in Keratinocytes to Induce Actin Stress Fiber Formation and Migration, Mol. Cell. Biol., 2005, vol. 25, pp. 60–65.
Zubova, Yu.G., Bykova, T.V., Zubova, S.G., Abramova, M.V., Aksenov, N.D., Pospelov, V.A., and Pospelova, T.V., Induction of the Premature Senescence Program by Inhibitor of Histone Deacetylases Sodium Butyrate in Normal and Transformed Rat Fibroblasts, Tsitologiya, 2005, vol. 47, no. 12, pp. 1055–1062.
Author information
Authors and Affiliations
Additional information
Original Russian Text © S.G. Zubova, T.V. Bykova, Yu.G. Zubova, V.S. Romanov, N.D. Aksenov, V.A. Pospelov, T.V. Pospelova, 2007, published in Tsitologiya, Vol. 49, No. 2, 2007.
Rights and permissions
About this article
Cite this article
Zubova, S.G., Bykova, T.V., Zubova, Y.G. et al. The role of p38 kinase in the activation of the premature senescence program in transformed mouse fibroblasts. Cell Tiss. Biol. 1, 151–161 (2007). https://doi.org/10.1134/S1990519X0702006X
Received:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X0702006X