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Contrary to belief, progesterone acts on endometrial genes only by activating protein kinases

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29
May
Thu, 29/05/2014 - 18:08

Contrary to belief, progesterone acts on endometrial genes only by activating protein kinases

  • Researchers from IByME-CONICET and the CRG have discovered how the endometrium responds to low levels of progestin hormones.
  • The work enables us to understand how endometrial cells proliferate in response to progestin, introducing the transcription factor progesterone receptor by cytoplasmic signalling.
  • The results have been published in PLoS ONE. 

For many years now, the endometrium was thought to be a target of nanomolar concentrations of the ovarian hormones progesterone and oestradiol, in order for it to grow each menstrual cycle, and prepare to receive a possible embryo. In this paper the authors describe a new mechanism that the progesterone receptor uses to induce stromal cell proliferation at picomolar progestin concentrations.
In a previous study the group did not find any transcriptional activity associated to the progesterone receptor in endometrial stromal cells that respond to progestin, so the work continued in order to explain the proliferative activity independently of its binding to chromatin.
After conducting their experiments, they concluded that progestin-induced proliferation of endometrial stromal cells is mediated by the kinases ERK1-2 and AKT, dependent on early regulation of USF1, which directly induces the cell cycle regulator Cdc2. "To our knowledge, this is the first description of early target genes of progestin-activated classical PR via crosstalk with protein kinases and independently of hormone receptor binding to the genomic targets", says Patricia Saragueta, co-author of the study and principal investigator at the IByME-CONICET.
The results in endometrial stromal cells are an example of the different ways used by steroid hormones, particularly progesterone, to modulate the activity of target genes.
"These cells have very little progesterone receptor although it is enough to trigger cell proliferation through the route described in the paper. This finding highlights the importance of kinase signalling for genomic hormone effects", says Miguel Beato, co-author of the study and head of the Chromatin and Gene Expression lab at the CRG.
"By clinical standards, the cells we used would have been considered negative for the progesterone receptor, and yet the cells respond to hormone stimulation. This could also apply to breast cancer cells with very low levels of hormone receptors", he adds.
Reference:
Vallejo G, La Greca AD, Tarifa-Reischle IC, Mestre-Citrinovitz AC, Ballaré C, et al. (2014) CDC2 Mediates Progestin Initiated Endometrial Stromal Cell Proliferation: A PR Signaling to Gene Expression Independently of Its Binding to Chromatin. PLoS ONE 9(5): e97311. doi:10.1371/journal.pone.0097311
For further information:
Flavia Hernandez - Press Officer – 54-11-47832869
flavia.hernandez@ibyme.conicet.gov.ar
Juan Sarasua
Press Officer - Centre for Genomic Regulation - CRG
juan.sarasua@crg.eu
Glossary:
"Immediate early genes" are those where the mRNA levels quickly respond to hormone fluctiations..
Stromal cells are connective tissue cells, like the endometrium, the ovary,and the bone marrow, and they support the functional cells.
IBYME-CONICET stands for Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.