Transcriptional Hyperactivity of Human Progesterone Receptors Is Coupled to Their Ligand-Dependent Down-Regulation by Mitogen-Activated Protein Kinase-Dependent Phosphorylation of Serine 294

doi:10.1128/MCB.21.18.6122-6131.2001

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Molecular and Cellular Biology, September 2001, p. 6122-6131, Vol. 21, No. 18
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.18.6122-6131.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transcriptional Hyperactivity of Human Progesterone Receptors Is Coupled to Their Ligand-Dependent Down-Regulation by Mitogen-Activated Protein Kinase-Dependent Phosphorylation of Serine 294

Tianjie Shen,¹ Kathryn B. Horwitz,¹ and Carol A. Lange²^,^*

Department of Medicine, The Molecular Biology Program, and The Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262,¹ and Department of Medicine, Department of Pharmacology, and The University of Minnesota Cancer Center, Minneapolis, Minnesota 55455²

Received 13 February 2001/Returned for modification 30 March 2001/Accepted 31 May 2001

Breast cancers often exhibit elevated expression of tyrosine kinase growth factor receptors; these pathways influence breastcancer cell growth in part by targeting steroid hormone receptors,including progesterone receptors (PR). To mimic activation ofmolecules downstream of growth factor-initiated signaling pathways,we overexpressed mitogen-activated protein kinase (MAPK; alsoknown as extracellular signal-regulated kinase) kinase kinase1 (MEKK1) in T47D human breast cancer cells expressing the B isoformof PR. MEKK1 is a strong activator of p42 and p44 MAPKs. MEKK1expression increased progestin-mediated transcription 8- to 10-foldabove normal PR-driven transcription levels. This was dependenton the presence of a progesterone response element and functionalPR. PR protein levels were unchanged by MEKK1 alone but were extensivelydown-regulated by MEKK1 plus the progestin R5020. MEKK1 expressionresulted in phosphorylation of PR on Ser294, a MAPK consensussite known to mediate ligand-dependent PR degradation. MEK inhibitorsblocked phosphorylation of Ser294 and attenuated PR transcriptionalhyperactivity in response to MEKK1 plus R5020; stabilization ofPR by inhibition of the 26S proteasome produced similar results.T47D cells stably expressing mutant S294A PR, in which serine294 is replaced by alanine, fail to undergo ligand-dependent down-regulationand are resistant to MEKK1-plus-R5020-induced transcriptionalsynergy but respond to progestins alone. Similarly, c-myc proteinlevels are synergistically increased by epidermal growth factorand R5020 in cells expressing wild-type PR, but not S294A PR.Thus, highly stable mutant PR are functional in response to progestinsbut are incapable of cross talk with MAPK-driven pathways. Thesestudies demonstrate a paradoxical coupling between steroid receptordown-regulation and transcriptional hyperactivity. They also suggesta link between phosphorylation of PR by MAPKs in response to peptidegrowth factor signaling and steroid hormone control of breastcancer cellgrowth.

^* Corresponding author. Mailing address: Department of Medicine, Department of Pharmacology, and The University of MinnesotaCancer Center, Mayo Mail Code 806, 420 Delaware St. SE, MinneapolisMN 55455. Phone: (612) 626-0621. Fax: (612) 624-3913. E-mail:Lange047{at}tc.umn.edu.

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