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1.
Proc Natl Acad Sci U S A ; 119(14): e2113520119, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35349341

RESUMO

SignificanceClassic serine proteases are synthesized as inactive precursors that are proteolytically processed, resulting in irreversible activation. We report an alternative and reversible mechanism of activation that is executed by an inactive protease. This mechanism involves a protein complex between the serine protease HTRA1 and the cysteine protease calpain 2. Surprisingly, activation is restricted as it improves the proteolysis of soluble tau protein but not the dissociation and degradation of its amyloid fibrils, a task that free HTRA1 is efficiently performing. These data exemplify a challenge for protein quality control proteases in the clearing of pathogenic fibrils and suggest a potential for unexpected side effects of chemical modulators targeting PDZ or other domains located at a distance to the active site.


Assuntos
Calpaína , Serina Endopeptidases , Amiloide/metabolismo , Calpaína/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/química , Proteólise , Serina Endopeptidases/metabolismo , Serina Proteases/metabolismo
2.
BMC Cancer ; 16: 399, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27388476

RESUMO

BACKGROUND: Increased numbers and improperly positioned centrosomes, aneuploidy or polyploidy, and chromosomal instability are frequently observed characteristics of cancer cells. While some aspects of these events and the checkpoint mechanisms are well studied, not all players have yet been identified. As the role of proteases other than the proteasome in tumorigenesis is an insufficiently addressed question, we investigated the epigenetic control of the widely conserved protease HTRA1 and the phenotypes of deregulation. METHODS: Mouse embryonal fibroblasts and HCT116 and SW480 cells were used to study the mechanism of epigenetic silencing of HTRA1. In addition, using cell biological and genetic methods, the phenotypes of downregulation of HTRA1 expression were investigated. RESULTS: HTRA1 is epigenetically silenced in HCT116 colon carcinoma cells via the epigenetic adaptor protein MBD2. On the cellular level, HTRA1 depletion causes multiple phenotypes including acceleration of cell growth, centrosome amplification and polyploidy in SW480 colon adenocarcinoma cells as well as in primary mouse embryonic fibroblasts (MEFs). CONCLUSIONS: Downregulation of HTRA1 causes a number of phenotypes that are hallmarks of cancer cells suggesting that the methylation state of the HtrA1 promoter may be used as a biomarker for tumour cells or cells at risk of transformation.


Assuntos
Neoplasias do Colo/genética , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Fibroblastos/citologia , Serina Endopeptidases/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Centrossomo/metabolismo , Neoplasias do Colo/patologia , Regulação para Baixo , Epigênese Genética , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Camundongos , Transplante de Neoplasias , Poliploidia , Regiões Promotoras Genéticas
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