ArticleMolecular and cellular biology2001
Transcriptional hyperactivity of human progesterone receptors is coupled to their ligand-dependent down-regulation by mitogen-activated protein kinase-dependent phosphorylation of serine 294.
Article in Molecular and cellular biology, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 203 citations in OpenAlex.
- Preoperative onapristone-XR in postmenopausal women with progesterone receptor-positive (PgR+)/HER2-negative early breast cancer: SOLTI-1802 ONAWA trial results.NPJ breast cancer · 2026Article
- MAP3K1: A Multifunctional Kinase at the Crossroads of Cancer Progression and Tumor Suppression.Cells · 2026Review
- Hormone receptor profile of ectopic and eutopic endometrium in adenomyosis: a systematic review.Human reproduction open · 2025Article
- Sensorimotor Development in Rat Neonates Exposed to 17-α-Hydroxyprogesterone Caproate: A Progestin Used in Obstetrics.Neuroendocrinology · 2025Article
- Regulatory mechanisms of steroid hormone receptors on gene transcription through chromatin interaction and enhancer reprogramming.Cellular oncology (Dordrecht, Netherlands) · 2024Review
- Site-specific O-GlcNAcylation of progesterone receptor (PR) supports PR attenuation of interferon stimulated genes (ISGs) and tumor growth in breast cancer.The Journal of biological chemistry · 2024Article
- Progesterone (P4) ameliorates cigarette smoke-induced chronic obstructive pulmonary disease (COPD).Molecular medicine (Cambridge, Mass.) · 2024Article
- PRMT1, a Key Modulator of Unliganded Progesterone Receptor Signaling in Breast Cancer.International journal of molecular sciences · 2022Article
- Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease.Endocrine reviews · 2022Review
- Enhancing progestin therapy via HDAC inhibitors in endometrial cancer.American journal of cancer research · 2022Article
- Progesterone modulates neuronal excitability bidirectionally.Neuroscience letters · 2021Review
- 90 YEARS OF PROGESTERONE: Steroid receptors as MAPK signaling sensors in breast cancer: let the fates decide.Journal of molecular endocrinology · 2020Review
- PRMT1 Is Critical for the Transcriptional Activity and the Stability of the Progesterone Receptor.iScience · 2020Article
- FGFs/FGFRs-dependent signalling in regulation of steroid hormone receptors - implications for therapy of luminal breast cancer.Journal of experimental & clinical cancer research : CR · 2019Review
- Sialic Acid-Binding Lectin from Bullfrog Eggs Exhibits an Anti-Tumor Effect Against Breast Cancer Cells Including Triple-Negative Phenotype Cells.Molecules (Basel, Switzerland) · 2018Article
- Transcriptional regulation ofThe Journal of biological chemistry · 2018Article
- Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer.Molecular cancer therapeutics · 2018Article
- Progestin and Nuclear Progestin Receptor Are Essential for Upregulation of Metalloproteinase in Zebrafish Preovulatory Follicles.Frontiers in endocrinology · 2018Article
- Gene expression effects of glucocorticoid and mineralocorticoid receptor agonists and antagonists on normal human skeletal muscle.Physiological genomics · 2017Article
- Posttranslationally modified progesterone receptors direct ligand-specific expression of breast cancer stem cell-associated gene programs.Journal of hematology & oncology · 2017Article
35 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
Abstract
Breast cancers often exhibit elevated expression of tyrosine kinase growth factor receptors; these pathways influence breast cancer cell growth in part by targeting steroid hormone receptors, including progesterone receptors (PR). To mimic activation of molecules downstream of growth factor-initiated signaling pathways, we overexpressed mitogen-activated protein kinase (MAPK; also known as extracellular signal-regulated kinase) kinase kinase 1 (MEKK1) in T47D human breast cancer cells expressing the B isoform of PR. MEKK1 is a strong activator of p42 and p44 MAPKs. MEKK1 expression increased progestin-mediated transcription 8- to 10-fold above normal PR-driven transcription levels. This was dependent on the presence of a progesterone response element and functional PR. PR protein levels were unchanged by MEKK1 alone but were extensively down-regulated by MEKK1 plus the progestin R5020. MEKK1 expression resulted in phosphorylation of PR on Ser294, a MAPK consensus site known to mediate ligand-dependent PR degradation. MEK inhibitors blocked phosphorylation of Ser294 and attenuated PR transcriptional hyperactivity in response to MEKK1 plus R5020; stabilization of PR by inhibition of the 26S proteasome produced similar results. T47D cells stably expressing mutant S294A PR, in which serine 294 is replaced by alanine, fail to undergo ligand-dependent down-regulation and are resistant to MEKK1-plus-R5020-induced transcriptional synergy but respond to progestins alone. Similarly, c-myc protein levels are synergistically increased by epidermal growth factor and R5020 in cells expressing wild-type PR, but not S294A PR. Thus, highly stable mutant PR are functional in response to progestins but are incapable of cross talk with MAPK-driven pathways. These studies demonstrate a paradoxical coupling between steroid receptor down-regulation and transcriptional hyperactivity. They also suggest a link between phosphorylation of PR by MAPKs in response to peptide growth factor signaling and steroid hormone control of breast cancer cell growth.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.