Tesis doctoral de Caroline Elisabeth Nunes-xavier
Controlled tyrosine phosphorylation is required for many cell processes such as growth, differentiation, and survival, and its balance is coordinated by the activities of tyrosine kinases (tks), and protein tyrosine phosphatases (ptps). Increased tyrosine phosphorylation has been correlated with many human diseases, including cancer. In general, the increased tk activation can be antagonized by the action of the ptps. However, in some cases the ptps can also potentiate the activation of the tks. in this study, we report the up-regulation of the protein tyrosine phosphatases ptp epsilon, mkp3, dusp5, and dusp13, in various human breast cancer cell lines, as well as in other cancer cells, in response to the phorbol ester pma. Up-regulation of ptp epsilon, mkp3 and dusp5 by pma in mcf-7 cells required the prolonged activation of the erk1/2 pathway, and correlated with the inhibition of this route, while up-regulation of dusp13b required the activation of the p38 pathway. Mkp3 induction relied on the activation of the ets2 transcription factor, whereas dusp5 induction depended on the activation of c-jun. mcf-7 cell lines expressing inducible high levels of ectopic ptp epsilon displayed altered adhesion properties, augmented anchorage-independent growth in soft agar, and increased erk1/2 activation. Conversely, diminishing the expression of ptp epsilon reduced anchorage-independent growth, and retained the cells in g0-g1-phase, decreased cell survival and induced apoptosis, and diminished erk1/2 and akt activation. Mcf-7 cell lines expressing high levels of mkp3 or dusp5 did not undergo pma-triggered growth arrest, displayed a migratory phenotype, formed colonies in soft agar, and showed inhibition of erk1/2 activation. Diminishing the expression of mkp3 or dusp5 raised the activation of erk1/2, and accelerated growth arrest of pma-treated mcf-7 cells. our results demonstrate opposing actions of distinct ptps in mcf-7 cells: ptp epsilon operates in a positive feedback loop to maintain erk1/2 and akt active; and mkp3 and dusp5 operate in a negative feedback loop shutting down erk1/2 activation. This suggests important roles for ptp epsilon, mkp3 and dusp5 in the control of proliferation and survival of human breast cancer cells.
Datos académicos de la tesis doctoral «Protein tyrosine phosphatases in human breast cancer cells«
- Título de la tesis: Protein tyrosine phosphatases in human breast cancer cells
- Autor: Caroline Elisabeth Nunes-xavier
- Universidad: Universitat de valéncia (estudi general)
- Fecha de lectura de la tesis: 12/07/2011
Dirección y tribunal
- Director de la tesis
- Rafael Pulido Murillo
- Tribunal
- Presidente del tribunal: wiljan Hendriks
- rosario Perona abellon (vocal)
- frank Bí¶hmer (vocal)
- Jaime Font de mora sainz (vocal)