Expression of the Calcium-Binding Protein CALB1 Is Induced and Controls Intracellular Ca2+ Levels in Senescent Cells

In response to many stresses, such as oncogene activation or DNA damage, cells can enter cellular senescence, a state of proliferation arrest accompanied by a senescence-associated secretory phenotype (SASP). Cellular senescence plays a key role in many physiopathological contexts, including Cancer, aging and aging-associated diseases, therefore, it is critical to understand how senescence is regulated. Calcium ions (CA²⁺) recently emerged as pivotal regulators of cellular senescence. However, how CA²⁺ levels are controlled during this process is barely known. Here, we report that intracellular CA²⁺ contents increase in response to many senescence inducers in immortalized human mammary epithelial cells (HMECs) and that expression of calbindin 1 (CALB1), a CA²⁺-binding protein, is upregulated in this context, through the CA²⁺-dependent Calcineurin/NFAT pathway. We further show that overexpression of CALB1 buffers the rise in intracellular CA²⁺ levels observed in senescent cells. Finally, we suggest that increased expression of CA²⁺-binding proteins calbindins is a frequent MARK of senescent cells. This work thus supports that, together with CA²⁺channels, CA²⁺-binding proteins modulate CA²⁺ levels and flux during cellular senescence. This opens potential avenues of research to better understand the role of CA²⁺ and of CA²⁺-binding proteins in regulating cellular senescence.