PKCα and PKCδ Activation Regulates Transcriptional Activity and Degradation of Progesterone Receptor in Human Astrocytoma Cells

Author:

González-Arenas Aliesha1,Peña-Ortiz Miguel Ángel1,Hansberg-Pastor Valeria1,Marquina-Sánchez Brenda1,Baranda-Ávila Noemi2,Nava-Castro Karen1,Cabrera-Wrooman Alejandro1,González-Jorge Jesús1,Camacho-Arroyo Ignacio1

Affiliation:

1. Departamento de Biología (A.G.-A., M.A.P.-O., V.H.-P., B.M.-S., K.N.-C., A.C.-W., J.G.-J., I.C.-A.), Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán 04510, Distrito Federal, México;

2. División de Investigación Básica (N.B.-A.), Instituto Nacional de Cancerología, México City 14080, Distrito Federal, México

Abstract

Abstract Progesterone regulates cancer cell proliferation and invasion through its receptors (PR-A and PR-B), whose phosphorylation modifies their transcriptional activity and induce their degradation. We identified by in silico analysis a putative residue (Ser400) in PR that might be phosphorylated by protein kinase C (PKC), a family of enzymes involved in the proliferation and infiltration of astrocytomas, the most frequent and aggressive brain tumors. A grade III human astrocytoma-derived cell line was used to study the role of PKC in PR phosphorylation, transcriptional activity, and degradation. Treatment with PKC activator [tetradecanoyl phorbol acetate (TPA)] increased PR phosphorylation in Ser400 after 5 minutes, which in turn induced PR transcriptional activity and its subsequent degradation by the 26S proteasome 3–5 hours after treatment. Silencing or inhibition of PKCα and PKCδ blocked PR phosphorylation and degradation induced by TPA. Both PR isoforms were associated with PKCα and reached the maximum association after 5 minutes of TPA addition. These data correlated with immunnofluorescence assays in which nuclear colocalization of PKCα with PR increased after TPA treatment. We observed a 2-fold increase in cell proliferation after PKC activation with TPA that was reduced with the PR antagonist, RU486. The PR S400A mutant revealed that this residue is essential for PKC-mediated PR phosphorylation and degradation. Our results show a key participation of PKCα and PKCδ in PR regulation and function.

Publisher

The Endocrine Society

Subject

Endocrinology

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