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Endocrinology Vol. 143, No. 4 1386-1403
Copyright © 2002 by The Endocrine Society

INTRACELLULAR SIGNAL SYSTEMS

Proteasome Implication in Phorbol Ester- and GnRH-Induced Selective Down-Regulation of PKC ({alpha}, {epsilon}, {zeta}) in {alpha}T3-1 and LßT2 Gonadotrope Cell Lines

Brice Junoy, Helene Maccario, Jean-Louis Mas, Alain Enjalbert and Sophia V. Drouva

Centre National de la Recherche Scientifique UMR 6544, Université de la Méditerranée, Faculté de Médecine, 13916 Marseille, France

Address all correspondence and requests for reprints to: S. V. Drouva, Interactions Cellulaires Neuroendocrieniennes, UMR 6544 Centre National de la Recherche Scientifique, IFR Jean-Roche, Fac Med Nord, Bd P. Dramard, 13916 Marseille Cedex 20, France. E-mail: . drouva.sv{at}jean-roche.univ-mrs.fr

We investigated mechanisms underlying selective down-modulation of PKC isoforms ({alpha}, {epsilon}, {zeta}): 1) during 12-O-tetradecanoyl-phorbol-13 acetate (TPA) (10-7 M) or GnRH (10-7 M) desensitization conditions (2- to 6-h treatments) in two gonadotrope cell lines ({alpha}T3-1, LßT2) and 2) in primary pituitary cell cultures from male rats during long-term phorbol ester administration. We demonstrated that, as in {alpha}T3-1 cells, in a more differentiated gonadotrope cell line LßT2 the GnRH-receptor coupling (PLC, PLA2, PLD) generated second messengers essential for PKCs activation; the characterized isoforms ({alpha}, ßII, {delta}, {epsilon}, {zeta}) were selectively and differentially down-regulated by TPA ({alpha}, ßII, {delta}, {epsilon}) or GnRH ({delta}, {epsilon}). In whole cell lysates, proteasome inhibitors (proteasome inhibitor I and II, Lactacystin, ß-Lactone, Calpain inhibitor I) prevented in both gonadotrope cell lines the TPA-induced depletion of PKC {alpha}, {epsilon}, and the GnRH-elicited PKC {epsilon} down-regulation; they counteracted in mixed pituitary cell cultures as well, the TPA-evoked PKC {alpha}, {epsilon} depletion. In contrast, the inhibitors of calpain(s) and lysosomal proteases (Calpeptin, E64d, Calpain inhibitor II, and PD150606), were ineffective. As shown in {alpha}T3-1 subcellular fractions, proteasome abrogation did not affect membrane translocation of TPA- and GnRH- target isoforms ({alpha}, {epsilon}) but, preventing their degradation, favored enzyme accumulation to the membrane compartment. Proteolysis processing of PKCs may be dependent upon their phosphorylated state and/or catalytic activity. Inhibition of PKC catalytic activity (GF109203X, Gö6976), selectively prevented the TPA-evoked PKC{alpha} depletion in both mixed pituitary cells and {alpha}T3-1 gonadotropes; in {alpha}T3-1 subcellular fractions, PKC{alpha} inactivation overcame the TPA-evoked isoenzyme degradation by inducing a pronounced membrane accumulation of the isoform without affecting its membrane relocalization. Thus, the proteasome system by adjusting PKC cellular levels, may represent a regulatory proteolytic pathway implicated in the adaptive mechanisms of the time dependent cell responses.




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