PMID- 10655479
OWN - NLM
STAT- MEDLINE
DCOM- 20000302
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 3
DP  - 2000 Feb 1
TI  - Phosphorylation of human progesterone receptors at serine-294 by
      mitogen-activated protein kinase signals their degradation by the 26S proteasome.
PG  - 1032-7
AB  - Ligand-dependent down-regulation that leads to rapid and extensive loss of
      protein is characteristic of several nuclear steroid receptors, including human
      progesterone receptors (PRs). In breast cancer cells, >95% of PRs are degraded 6 
      h after the start of progestin treatment. The mechanism for down-regulation is
      unknown. We examined the role of PR phosphorylation by mitogen-activated protein 
      kinases (MAPKs) in this process. Lactacystin and calpain inhibitor I, specific
      inhibitors of the 26S proteasome, blocked progestin-induced down-regulation, and 
      ubiquitinated conjugates of PR accumulated in cells. Ligand-dependent PR
      degradation was also blocked by specific inhibition of p42 and p44 MAPKs. To
      define the targets of phosphorylation by this kinase, two serine/proline MAPK
      consensus sites on PR were mutated. We demonstrate that mutation of PR serine-294
      to alanine (S294A) specifically and completely prevents ligand-dependent receptor
      down-regulation. We also find that rapid, ligand-independent degradation of
      immature PR intermediates occurs by a proteasome-mediated pathway. These results 
      demonstrate that PR destruction, by either of two alternate routes, is mediated
      by the 26S proteasome. Specifically, down-regulation of mature PRs occurs by a
      mechanism in which ligand binding activates PR phosphorylation by MAPKs at a
      unique serine residue, which then targets the receptors for degradation.
FAU - Lange, C A
AU  - Lange CA
AD  - Department of Medicine, The Molecular Biology Program, and The Colorado Cancer
      Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
FAU - Shen, T
AU  - Shen T
FAU - Horwitz, K B
AU  - Horwitz KB
LA  - eng
GR  - DK53825/DK/NIDDK NIH HHS/United States
GR  - DK48238/DK/NIDDK NIH HHS/United States
GR  - R01 CA026869/CA/NCI NIH HHS/United States
GR  - R37 CA026869/CA/NCI NIH HHS/United States
GR  - R01 DK053825/DK/NIDDK NIH HHS/United States
GR  - CA26869/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Glycoproteins)
RN  - 0 (Imidazoles)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, Progesterone)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Ubiquitins)
RN  - 0 (calpain inhibitors)
RN  - 133343-34-7 (lactacystin)
RN  - 17885-08-4 (Phosphoserine)
RN  - 9XE0V2SQYX (Promegestone)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - OU13V1EYWQ (SB 203580)
RN  - PVX798P8GI (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/analogs & derivatives/pharmacology
MH  - Breast Neoplasms/chemistry
MH  - Consensus Sequence
MH  - Cysteine Endopeptidases/drug effects/*metabolism
MH  - Down-Regulation/*physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Glycoproteins/pharmacology
MH  - HeLa Cells/metabolism
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - *MAP Kinase Signaling System
MH  - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/metabolism
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
MH  - Multienzyme Complexes/drug effects/*metabolism
MH  - Neoplasm Proteins/*metabolism
MH  - Phosphorylation
MH  - Phosphoserine/*chemistry
MH  - Promegestone/pharmacology
MH  - Proteasome Endopeptidase Complex
MH  - Protein Isoforms/*metabolism
MH  - *Protein Processing, Post-Translational
MH  - Pyridines/pharmacology
MH  - Receptors, Progesterone/chemistry/*metabolism
MH  - Recombinant Fusion Proteins/metabolism
MH  - Ubiquitins/metabolism
PMC - PMC15511
EDAT- 2000/02/03 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/02/03 09:00
PHST- 2000/02/03 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/02/03 09:00 [entrez]
AID - 10.1073/pnas.97.3.1032 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1032-7. doi: 10.1073/pnas.97.3.1032.