Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity.
The relationship of the classical receptors and their transcriptional activity to nongenotropic effects of steroid hormones is unknown. We demonstrate herein a novel paradigm of sex steroid action on osteoblasts, osteocytes, embryonic fibroblasts, and HeLa cells involving activation of a Src/Shc/ERK signaling pathway and attenuating apoptosis. This action is mediated by the ligand binding domain and eliminated by nuclear targeting of the receptor protein; ERalpha, ERbeta, or AR can transmit it with similar efficiency irrespective of whether the ligand is an estrogen or an androgen. This antiapoptotic action can be dissociated from the transcriptional activity of the receptor with synthetic ligands, providing proof of principle for the development of function-specific-as opposed to tissue-selective-and gender-neutral pharmacotherapeutics.
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic, Bone Diseases, University of Arkansas for Medical Sciences and, the Central Arkansas Veterans Health Care, System, Little Rock, AR 72205, USA.
S
S
Kousteni
T
T
Bellido
L I
LI
Plotkin
C A
CA
O'Brien
D L
DL
Bodenner
L
L
Han
K
K
Han
G B
GB
DiGregorio
J A
JA
Katzenellenbogen
B S
BS
Katzenellenbogen
P K
PK
Roberson
R S
RS
Weinstein
R L
RL
Jilka
S C
SC
Manolagas
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D018909:src Homology Domains / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism
D000728:Androgens; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D010446:Peptide Fragments; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases