PKCθ-induced phosphorylations control the ability of Fra-1 to stimulate gene expression and cancer cell migration.
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.
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.
Karine
K
Belguise
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.
Sara
S
Cherradi
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.
Awa
A
Sarr
Unité de Recherche Translationnelle, Institut Régional du Cancer de Montpellier, Montpellier, F-34298, France.
Florence
F
Boissière
Département de Biopathologie, CHU Montpellier, Montpellier, F-34295, France.
Nathalie
N
Boulle
Unité de Recherche Translationnelle, Institut Régional du Cancer de Montpellier, Montpellier, F-34298, France.
Joëlle
J
Simony-Lafontaine
LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062, Toulouse, France.
Valérie
V
Choesmel-Cadamuro
LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062, Toulouse, France.
Xiaobo
X
Wang
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.
Dany
D
Chalbos
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D055550:Protein Stability; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D000099169:Fos-Related Antigen 1
D014408:Biomarkers, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases; D015850:Interleukin-6; D007527:Isoenzymes; D020781:Matrix Metalloproteinase 1; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1; C508600:IL6 protein, human; C076233:PRKCQ protein, human; C522360:MMP1 protein, human
Breast cancer; Cell migration; Post-transcriptional regulation; Transcriptional activity