Редактирование: BTK (раздел)

==Publications==

{{medline-entry
|title=Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31736210
|abstract=One of the hallmarks of aging is the progressive accumulation of senescent cells in organisms, which has been proposed to be a contributing factor to age-dependent organ dysfunction. We recently reported that Bruton's tyrosine kinase ([[BTK]]) is an upstream component of the p53 responses to DNA damage. [[BTK]] binds to and phosphorylates p53 and [[MDM2]], which results in increased p53 activity. Consistent with this, blocking [[BTK]] impairs p53-induced senescence. This suggests that sustained [[BTK]] inhibition could have an effect on organismal aging by reducing the presence of senescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalent inhibitor of [[BTK]], prolonged the maximum lifespan of a Zmpste24  progeroid mice, which also showed a reduction in general age-related fitness loss. Importantly, we found that certain brain functions were preserved, as seen by reduced anxiety-like behaviour and better long-term spatial memory. This was concomitant to a decrease in the expression of specific markers of senescence in the brain, which confirms a lower accumulation of senescent cells after [[BTK]] inhibition. Our data show that blocking [[BTK]] has a modest increase in lifespan in Zmpste24  mice and protects them from a decline in brain performance. This suggests that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age-related degeneration of organs such as the brain.

|keywords=* BTK
* cellular senescence
* healthspan
* p53
* progeria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974713
}}
{{medline-entry
|title=[[BTK]] suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28915637
|abstract=We previously explored the role of [[BTK]] in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of [[BTK]] suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of [[BTK]] in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, [[BTK]] high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts. Knockdown [[BTK]] expression by shRNA induced MM cellular senescence using β-galactosidase (SA-b-gal) staining, cell growth arrest by cell cycle staining and decreased clonogenicity while forcing [[BTK]] expression in MM cells abrogated these characteristics. We also validated this feature in mouse embryonic fibroblast cells (MEFs), which showed that elevated [[BTK]] expression was resistant to MEF senescence after serial cultivation [i]in vitro[/i]. Further mechanism study revealed that [[BTK]] activated AKT signaling leading to down-regulation of P27 expression and hindered RB activity while AKT inhibitor, LY294002, overcame [[BTK]]-overexpression induced cellular senescence resistance. Eventually we demonstrated that [[BTK]] inhibitor, CGI-1746, induced MM cellular senescence, colony reduction and tumorigenecity inhibition [i]in vivo[/i]. Summarily, we designate a novel mechanism of [[BTK]] in mediating MM growth, and [[BTK]] inhibitor is of great potential [i]in vivo[/i] and [i]in vitro[/i] suggesting [[BTK]] is a promising therapeutic target for MM.

|keywords=* AKT
* BTK
* CGI-1746
* multiple myeloma
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593608
}}