A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis.
Endometriosis is considered to be an estrogen-dependent inflammatory disease, but its etiology is unclear. Thus far, a mechanistic role for steroid receptor coactivators (SRCs) in the progression of endometriosis has not been elucidated. An SRC-1-null mouse model reveals that the mouse SRC-1 gene has an essential role in endometriosis progression. Notably, a previously unidentified 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from patients with endometriosis compared to normal endometrium. Tnf⁻/⁻ and Mmp9⁻/⁻ mice with surgically induced endometriosis showed that activation of tumor necrosis factor a (TNF-α)-induced matrix metallopeptidase 9 (MMP9) activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α-mediated apoptosis in human endometrial epithelial cells and causes the epithelial-mesenchymal transition and the invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the newly identified TNF-α-MMP9-SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Sang Jun
SJ
Han
Shannon M
SM
Hawkins
Khurshida
K
Begum
Sung Yun
SY
Jung
Ertug
E
Kovanci
Jun
J
Qin
John P
JP
Lydon
Francesco J
FJ
DeMayo
Bert W
BW
O'Malley
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002828:Choristoma / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004715:Endometriosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D004717:Endometrium / Q000201:enzymology / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism*; D020033:Protein Isoforms; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D056920:Nuclear Receptor Coactivator 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9