Abstract
Proliferation of nontransformed cells is regulated by cell–cell contacts, which are referred to as contact-inhibition. Despite its generally accepted importance for cell cycle control, knowledge about the intracellular signalling pathways involved in contact inhibition is scarce. In the present work we show that p38α mitogen-activated protein kinase (MAPK) is involved in the growth-inhibitory signalling cascade of contact inhibition in fibroblasts. p38α activity is increased in confluent cultures of human fibroblasts compared to proliferating cultures. Time course studies show a sustained activation of p38α in response to cell–cell contacts in contrast to a transient activation after serum stimulation. The induction of contact inhibition by addition of glutaraldehyde-fixed cells is impaired by pharmacological inhibition of p38 as well as in p38α−/− fibroblasts. Further evidence for a central role of p38α in contact inhibition comes from the observation that p38α−/− fibroblasts show a higher saturation density compared to wild-type (wt) fibroblasts, which is reversed by reconstituted expression of p38α. In agreement with a defect in contact inhibition, p27Kip1 accumulation is impaired in p38α−/− fibroblasts compared to wt fibroblasts. Hence, our work shows a new role for p38α in contact inhibition and provides a mechanistic basis for the recently proposed tumour suppressive function of this MAPK pathway.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abercrombie M . (1979). Nature, 281, 259–262.
Ambrosino C and Nebreda AR . (2001). Biol. Cell, 93, 47–51.
Bulavin DV, Demidov O, Saito S, Kauraniemi P, Phillips C, Amundson S, Ambrosino C, Sauter G, Nebreda A, Anderson C, Kallioniemi A, Fornace Jr A and Appella E . (2002). Nat. Genet., 31, 210–215.
Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW, Appella E and Fornace Jr AJ . (2004). Nat. Genet., 36, 343–350.
Casanovas O, Miro F, Estanyol JM, Itarte E, Agel N and Bachs O . (2000). J. Biol. Chem., 275, 35091–35097.
Cohen P . (1997). Trends Cell Biol., 7, 353–361.
Conrad PW, Rust RT, Han J, Millhorn DE and Beitner-Johnson D . (1999). J. Biol. Chem., 274, 23570–23576.
Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher T, Young P and Lee JC . (1995). FEBS Lett., 364, 229–233.
Dietrich C, Bartsch T, Schanz F, Oesch F and Wieser R . (1996). Proc. Natl. Acad. Sci. USA, 93, 10815–10819.
Dietrich C, Wallenfang K, Oesch F and Wieser F . (1997). Oncogene, 15, 2743–2747.
Dulic V, Lees E and Reed SI . (1992). Science, 257, 1958–1961.
Eagle H and Levine E . (1967). Nature, 213, 1102–1106.
Ellinger-Ziegelbauer H, Kelly K and Siebenlist U . (1999). Mol. Cell. Biol., 19, 3857–3868.
Gradl G, Faust D, Oesch F and Wieser R . (1995). Curr. Biol., 5, 526–535.
Haq R, Brenton JD, Takahashi M, Finan D, Rottapel R and Zanke B . (2002). Cancer Res., 62, 5076–5082.
Heit I, Wieser R, Herget T, Faust D, Borchert-Stuhlträger M, Oesch F and Dietrich C . (2001). Oncogene, 20, 5143–5154.
Laemmli UK . (1970). Nature, 227, 680–685.
Lavoie JN, L’Allemain G, Brunet A, Müller R and Poussegur J . (1996). J. Biol. Chem., 271, 20608–20616.
Molnar A, Theodoras AM, Zon LI and Kyriakis JM . (1997). J. Biol. Chem., 272, 13229–13235.
Nakatsuji Y and Miller RH . (1998). Glia, 22, 379–389.
Nebreda AR and Porras A . (2000). Trends Biochem. Sci., 25, 257–260.
Oesch F, Janik-Schmitt B, Ludewig G, Glatt H-R and Wieser R . (1987). Eur. J. Cell Biol., 43, 403–407.
Ono K and Han J . (2000). Cell. Signal., 12, 1–13.
Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM and Koff A . (1994). Genes Dev., 8, 9–22.
Shi Y and Gaestel M . (2002). Biol. Chem., 383, 1519–1536.
Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ and Klenk DC . (1985). Anal. Biochem., 150, 76–85.
Wang XZ and Ron D . (1996). Science, 272, 1347–1349.
Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S and Sun P . (2002). Mol. Cell. Biol., 22, 3389–3403.
Wieser R, Heck R and Oesch F . (1985). Exp. Cell Res., 158, 493–499.
Wieser R and Oesch F . (1986). J. Cell Biol., 103, 361–367.
Wieser R, Schütz S, Tschank G, Dienes H-P, Thomas H and Oesch F . (1990). J. Cell Biol., 111, 2681–2692.
Wieser R, Baumann C and Oesch F . (1995). Glycoconjugate J., 12, 672–679.
Wieser R, Faust D, Dietrich C and Oesch F . (1999). Oncogene, 18, 277–281.
Acknowledgements
The expert technical assistance of Sandra Niemann and Emma Black is gratefully acknowledged. This work was supported by the Grant Di 793/1-2 by the Deutsche Forschungsgemeinschaft (CD), by a grant by the Stiftung Rheinland-Pfalz für Innovation (8312-386261/539) and by a grant of the Fundacion Cientifica de la Asociacion Española Contra el Cancer (ARN).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)
Supplementary information
Rights and permissions
About this article
Cite this article
Faust, D., Dolado, I., Cuadrado, A. et al. p38α MAPK is required for contact inhibition. Oncogene 24, 7941–7945 (2005). https://doi.org/10.1038/sj.onc.1208948
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208948
Keywords
This article is cited by
-
Together we stand, apart we fall: how cell-to-cell contact/interplay provides resistance to ferroptosis
Cell Death & Disease (2020)
-
Cell–cell contacts protect against t-BuOOH-induced cellular damage and ferroptosis in vitro
Archives of Toxicology (2019)
-
p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner
Scientific Reports (2017)
-
Deciphering fact from artifact when using reporter assays to investigate the roles of host factors on L1 retrotransposition
Mobile DNA (2016)
-
AhR-mediated changes in global gene expression in rat liver progenitor cells
Archives of Toxicology (2013)