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EMBO J. 2015 Jul 14;34(14):1875-88. doi: 10.15252/embj.201490594. Epub 2015 May 19.

Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid.

Author information

1
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
2
Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
3
Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain.
4
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain clo@uniovi.es.

Abstract

MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14(-/-) mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure. Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16(INK4a) and p21(CIP1/WAF) (1), increased activity of senescence-associated β-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations. Consistent with the role of retinoic acid signaling in nuclear lamina stabilization, treatment of Mmp14(-/-) mice with all-trans retinoic acid reversed the nuclear lamina alterations, partially rescued the cell senescence phenotypes, ameliorated the pathological defects in bone, skin, and heart, and extended their life span. These results demonstrate that nuclear architecture and cell senescence can be modulated by a membrane protease, in a process involving the ECM as a key regulator of nuclear stiffness under cell stress conditions.

KEYWORDS:

aging; extracellular matrix; metalloprotease; nuclear lamina; retinoids

PMID:
25991604
PMCID:
PMC4547893
DOI:
10.15252/embj.201490594
[Indexed for MEDLINE]
Free PMC Article

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