Cellular senescence of human mammary epithelial cells (HMEC) is associated with an altered MMP-7/HB-EGF signaling and increased formation of elastin-like structures.
The extracellular matrix (ECM) and a complex interplay of cell-to-cell and cell-to-matrix (ECM) interactions provide important platforms to determine cellular senescence and a potentially tumorigenic transformation of normal human mammary epithelial cells (HMEC). An enhanced formation of extracellular filaments, consisting of elastin-like structures, in senescent post-selection HMEC populations was paralleled by a significantly increased expression of its precursor protein tropoelastin and matched with a markedly elevated activity of the cross-linking enzyme family of lysyl oxidases (LOX). RNAi experiments revealed both the ECM metalloproteinase MMP-7 and the growth factor HB-EGF as potential effectors of an increased tropoelastin expression. Moreover, co-localization of MMP-7 and HB-EGF as well as a concomittant downstream signaling via Fra-1 indicated a possible association between the reduced MMP-7 enzyme activity and an impaired HB-EGF processing, resulting in an enhanced tropoelastin synthesis during senescence of HMEC. In agreement with previous work, these findings suggested an important influence of the extracellular proteinase MMP-7 on the aging process of HMEC, affecting both extracellular remodeling as well as intracellular signaling pathways.
Bertram
Catharina
C
Clinic of Obstetrics and Gynecology, Biochemistry and Tumor Biology Lab (OE6411), Medical School, D - 30625 Hannover, Germany.
Hass
Ralf
R
D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004549:Elastin / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology*; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology / Q000201:enzymology*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014333:Tropoelastin / Q000378:metabolism; D000099169:Fos-Related Antigen 1
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004549:Elastin; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020783:Matrix Metalloproteinase 7; D008249:Protein-Lysine 6-Oxidase; D016760:Proto-Oncogene Proteins c-fos; D014333:Tropoelastin; D000099169:Fos-Related Antigen 1; C587883:HBEGF protein, human; C060932:MMP7 protein, human