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Prolactin induces c-Myc expression and cell survival through activation of Src/Akt pathway in lymphoid cells

Oncogene volume 23, pages 7378–7390 (2004)Cite this article

Abstract

Stimulation of resting W53 cells (lymphoid murine cells expressing prolactin (PRL) receptor) by PRL induced expression of growth-related immediate-early genes (IEG), and proliferation through activation of the Src kinases. Since IEG are essential for cell cycle progression, we have studied how PRL controls expression of c-Myc mRNA and c-Fos. Stimulation of W53 cell proliferation by PRL required activation of MAPK, as the Mek1/2 inhibitor PD184352 eliminated Erk1/2 stimulation, cell proliferation, and expression of c-Fos mRNA. In contrast, PD184352 did not alter PRL activation of c-Myc mRNA expression or stimulation of p70S6K, Akt, and the Jak2/Stat5 pathway. Activation of the PI3K by PRL was necessary for the expression of c-MycmRNA and W53 cell proliferation, as the PI3K inhibitor LY294002 abolished them. However, it did not modify PRL stimulation of c-Fos mRNA expression or activation of Erk1/2 and Stat5. Furthermore, rapamycin, an inhibitor of mTOR and consequently of p70S6K, did not alter PRL stimulation of c-Myc and c-Fos mRNA expression and it had a very minor inhibitory effect on PRL stimulation of W53 cell proliferation. In addition, rapamycin did not affect PRL stimulation of Akt or Stat5. However, it reinforced PRL activation of Erk1/2. Overexpression of a constitutively activated Akt (myristoylated Akt) in W53 cells overcame the inhibitory effect of LY294002 on c-Myc expression, as well as cell death upon PRL deprivation. Consistently, inducible expression of Akt-CAAX Box in W53 cells caused inhibition of c-Myc expression. PRL stimulation of W53 cells resulted in Akt translocation to the nucleus, phosphorylation of FKHRL1 transcription factor, and its nuclear exclusion. In contrast, induced expression of Akt-CAAX Box caused inhibition of FKHRL1 phosphorylation. Furthermore, transient expression of nonphosphorylatable FKHRL1-A3 mutant impaired PRL-induced activation of the c-Myc promoter. Akt activation also resulted in phosphorylation and inhibition of glycogen synthetase kinase 3 (GSK3), which in turn promoted c-Myc stability. Consistently, treatment of W53 with selective inhibitors of GSK3 such as SB415286 and lithium salts resulted in increased levels of c-Myc. Also, overexpression of c-Myc in W53 cells overcame the decrease in cell proliferation induced by LY294002. These findings defined a PRL-signalling cascade in W53 cells, involving Src kinases/PI3K/Akt/FKHRL1-GSK3, that mediates stimulation of c-Myc expression.

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Acknowledgements

We thank B Burgering, A Mui, G Thomas, T Lee, and G Sonenshein for plasmids. G Thomas for the anti-p70S6K, L Litchkowic for anti-GSK3, F Wandosell for anti-P-GSK3 and SB415286, the NIDDK and Dr AF Parlow for the oPRL-20 used in these experiments, and J Pérez for the artwork. O Gjoerup, A Aranda, C Bernabeu, AC Carrera, and F Wandosell for helpful discussions. This work was supported by grants to JM-P from MCyT (PM99-0113, SAF2003-02188), CAM (08.1/0047/98) and FIS (01/1316), and grant to JL from MCyT (SAF2002-4193). JMGM was supported by a fellowship from FIS and LG was supported by a fellowship from Fundación Carolina.

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Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas, CSIC, Calle Arturo Duperier, 4, Madrid, 28029, Spain

    María Aurora Domínguez-Cáceres, José Manuel García-Martínez, Lorena González & Jorge Martín-Pérez

  2. Istituto Superiore di Sanitá, Viale Regina Elena, 299, Rome, 00161, Italy

    Annarica Calcabrini

  3. Servicio de Inmunologia, Hospital Universitario Ramón y Cajal, Madrid, Spain

    Pedro González Porque

  4. Departamento de Biología Molecular, Grupo de Biología Molecular del Cancer y Unidad de Biomedicina-CSIC, Facultad de Medicina, Universidad de Cantabria, Santander, Spain

    Javier León

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Correspondence to Jorge Martín-Pérez.

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Domínguez-Cáceres, M., García-Martínez, J., Calcabrini, A. et al. Prolactin induces c-Myc expression and cell survival through activation of Src/Akt pathway in lymphoid cells. Oncogene 23, 7378–7390 (2004). https://doi.org/10.1038/sj.onc.1208002

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