AKTIP
AKT-interacting protein (Ft1) (Fused toes protein homolog) [FTS]
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Human AKTIP and mouse Ft1 are orthologous ubiquitin E2 variant proteins involved in telomere maintenance and DNA replication. AKTIP also interacts with A- and B-type lamins. These features suggest that Ft1 may be implicated in aging regulatory pathways. Here, we show that cells derived from hypomorph Ft1 mutant (Ft1 ) mice exhibit telomeric defects and that Ft1 animals develop progeroid traits, including impaired growth, skeletal and skin defects, abnormal heart tissue, and sterility. We also demonstrate a genetic interaction between Ft1 and p53. The analysis of mice carrying mutations in both Ft1 and p53 (Ft1 ; p53 and Ft1 ; p53 ) showed that reduction in p53 rescues the progeroid traits of Ft1 mutants, suggesting that they are at least in part caused by a p53-dependent DNA damage response. Conversely, Ft1 reduction alters lymphomagenesis in p53 mutant mice. These results identify Ft1 as a new player in the aging process and open the way to the analysis of its interactions with other progeria genes using the mouse model.
MeSH Terms
- Animals
- Apoptosis Regulatory Proteins
- Cells, Cultured
- Gene Expression Profiling
- Mice
- Mice, Inbred C57BL
- Mutation
- Progeria
- Proteins
- Tumor Suppressor Protein p53
Keywords
- AKTIP
- DNA damage
- aging
- lamins
- progeria
- telomeres
AKTIP is a shelterin-interacting protein required for replication of telomeric DNA. Here, we show that AKTIP biochemically interacts with A- and B-type lamins and affects lamin A, but not lamin C or B, expression. In interphase cells, AKTIP localizes at the nuclear rim and in discrete regions of the nucleoplasm just like lamins. Double immunostaining revealed that AKTIP partially co-localizes with lamin B1 and lamin A/C in interphase cells, and that proper AKTIP localization requires functional lamin A. In mitotic cells, AKTIP is enriched at the spindle poles and at the midbody of late telophase cells similar to lamin B1. AKTIP-depleted cells show senescence-associated markers and recapitulate several aspects of the progeroid phenotype. Collectively, our results indicate that AKTIP is a new player in lamin-related processes, including those that govern nuclear architecture, telomere homeostasis and cellular senescence.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Apoptosis Regulatory Proteins
- Cells, Cultured
- Cellular Senescence
- Gene Expression Regulation
- Gene Knockdown Techniques
- HeLa Cells
- Humans
- Lamin Type A
- Lamin Type B
- Mitosis
- Nuclear Envelope
- Telomere
- Telomere Homeostasis
Keywords
- cell senescence
- lamin
- laminopathies
- nuclear lamina
- progeria
- telomeres