| RRC ID |
18923
|
| Author |
Yamazaki Y, Kamei Y, Sugita S, Akaike F, Kanai S, Miura S, Hirata Y, Troen BR, Kitamura T, Nishino I, Suganami T, Ezaki O, Ogawa Y.
|
| Title |
The cathepsin L gene is a direct target of FOXO1 in skeletal muscle.
|
| Journal |
Biochem J
|
| Abstract |
FOXO1 (forkhead box O1), a forkhead-type transcription factor whose gene expression is up-regulated in the skeletal muscle during starvation, appears to be a key molecule of energy metabolism and skeletal muscle atrophy. Cathepsin L, a lysosomal proteinase whose expression is also up-regulated in the skeletal muscle during starvation, is induced in transgenic mice overexpressing FOXO1 relative to wild-type littermates. In the present study, we conducted in vivo and in vitro experiments focusing on FOXO1 regulation of Ctsl (cathepsin L gene; CTSL1 in humans) expression in the skeletal muscle. During fasting and refeeding of C57BL/6 mice, Ctsl was regulated in parallel with FOXO1 in the skeletal muscle. Fasting-induced Ctsl expression was attenuated in transgenic mice overexpressing a dominant-negative form of FOXO1 or in skeletal-muscle-specific Foxo1-knockout mice relative to respective wild-type controls. Using C2C12 mouse myoblasts overexpressing a constitutively active form of FOXO1, we showed that FOXO1 induces Ctsl expression. Moreover, we found FOXO1-binding sites in both the mouse Ctsl and human CTSL1 promoters. The luciferase reporter analysis revealed that the mouse Ctsl and human CTSL1 promoters are activated by FOXO1, which is abolished by mutations in the consensus FOXO1-binding sites. Gel mobility-shift and chromatin immunoprecipiation assays showed that FOXO1 is recruited and binds to the Ctsl promoter. The present study provides in vivo and in vitro evidence that Ctsl is a direct target of FOXO1 in the skeletal muscle, thereby suggesting a role for the FOXO1/cathepsin L pathway in fasting-induced skeletal muscle metabolic change and atrophy.
|
| Volume |
427(1)
|
| Pages |
171-8
|
| Published |
2010-3-15
|
| DOI |
10.1042/BJ20091346
|
| PII |
BJ20091346
|
| PMID |
20088826
|
| MeSH |
Animals
Binding Sites
Blotting, Western
Cathepsin L / physiology*
Cells, Cultured
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
Female
Forkhead Box Protein O1
Forkhead Transcription Factors / physiology*
Gene Expression Regulation*
Humans
Luciferases / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Muscle, Skeletal / cytology
Muscle, Skeletal / metabolism*
Myoblasts / metabolism
Promoter Regions, Genetic / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
|
| IF |
4.097
|
| Times Cited |
35
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Human and Animal Cells |
C2C12(RCB0987) |
