Characterization of Matrix Metalloprotease 1a in Tumorigenesis.
Foley, Caitlin.
2014
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Abstract: Matrix metalloproteases (MMPs) are a family of extracellular proteases that allow cells to both sense and remodel their extracellular environment through cleavage of cell surface receptors, secreted factors and matrix proteins. While proteolytic activity of MMPs is required for normal tissue homeostasis and other physiologic processes, many pathophysiologic conditions are associated with... read moredysregulated MMP activity. While some diversity exists between vertebrate MMPs, animal models have been extensively utilized to characterize MMP signaling in disease. However, the study of MMP1, a tumorigenic collagenase and activator of protease activated receptor 1 (PAR1), has been limited in animal models due to uncertainty as to whether mouse MMP1 is functionally equivalent to human MMP1. In rodents, gene duplication has created to two potential MMP1 homologues, Mmp1a and Mmp1b. Mmp1b lacks enzymatic activity, suggesting that Mmp1a is the MMP1 homologue in tumorigenesis models. Mouse-derived lung cancer and melanoma cells expressed high levels of Mmp1a. Mmp1a expression promoted PAR1-driven collagen invasion and stellate growth in three-dimensional culture. Silencing of Mmp1a reduced in vivo tumorigenesis, invasion, and metastasis of mouse lung cancer cells, consistent with Mmp1a acting as an MMP1-like activity in tumor models. To better understand the functions of Mmp1a in vivo, Mmp1a-deficient animals were generated. Mmp1a-/- animals are healthy and fertile. Tumor growth and angiogenesis was reduced in Mmp1a-/- mice. This phenotype was present despite cancer cell Mmp1a expression and could be rescued by co-implantation of Mmp1a+/+ fibroblasts, highlighting the importance of stromal Mmp1a. Despite homologous MMP1-like functions in tumorigenesis models, Mmp1a expression was less than MMP1 in quiescent tissues. Mammalian expression systems revealed a severe defect in production of mature Mmp1a but not MMP1 protein. This defect was caused by instability of the Mmp1a prodomain, partially due to a phenylalanine to leucine prodomain substitution that interfaces with the catalytic domain. Together, these results demonstrate that Mmp1a is a relevant homologue for MMP1 in tumorigenesis models but also highlight key biochemical differences between MMP1 and Mmp1a that require further exploration for the development of relevant MMP1 mouse models of human disease.
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Genetics.
Advisor: Athan Kuliopulos.
Committee: Alain Charest, Phil Hinds, and Peter Brodeur.
Keyword: Genetics.read less - ID:
- xd07h577z
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