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Cancer Lett. 2017 Jan 28;385:97-107. doi: 10.1016/j.canlet.2016.10.038. Epub 2016 Nov 2.

PKCθ-induced phosphorylations control the ability of Fra-1 to stimulate gene expression and cancer cell migration.

Author information

1
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut de Cancérologie de Montpellier, Montpellier, F-34298, France. Electronic address: karine.belguise@univ-tlse3.fr.
2
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut de Cancérologie de Montpellier, Montpellier, F-34298, France.
3
Unité de Recherche Translationnelle, Institut Régional du Cancer de Montpellier, Montpellier, F-34298, France.
4
Département de Biopathologie, CHU Montpellier, Montpellier, F-34295, France.
5
LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062, Toulouse, France.
6
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34090, France; Institut de Cancérologie de Montpellier, Montpellier, F-34298, France. Electronic address: dany.chalbos@inserm.fr.

Abstract

The AP-1 transcription factor Fra-1 is aberrantly expressed in a large number of cancers and plays crucial roles in cancer development and progression by stimulating the expression of genes involved in these processes. However, the control of Fra-1 transactivation ability is still unclear and here we hypothesized that PKCθ-induced phosphorylation could be necessary to obtain a fully active Fra-1 protein. Using MCF7 stable cells overexpressing equivalent levels of unphosphorylated Fra-1 or PKCθ-phosphorylated Fra-1, we showed that PKCθ-induced phosphorylation of Fra-1 was crucial for the stimulation of MMP1 and IL6 expression. Consistently, we found a significant positive correlation between PRKCQ (coding for PKCθ) and MMP1 mRNA expression levels in human breast cancer samples. PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. More importantly, these phosphorylations were required for Fra-1-induced migration of breast cancer cells and phosphorylated Fra-1 expression was enriched at the invasion front of human breast tumors. Taken together, our findings indicate that PKCθ-induced phosphorylation could be important for the function of Fra-1 in cancer progression.

KEYWORDS:

Breast cancer; Cell migration; Post-transcriptional regulation; Transcriptional activity

PMID:
27816489
DOI:
10.1016/j.canlet.2016.10.038
[Indexed for MEDLINE]

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