Upregulation of Mcl-1S Causes Cell-Cycle Perturbations and DNA Damage AccumulationстатьяЭлектронная публикация
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 10 февраля 2021 г.
Аннотация:As an important regulator of apoptosis, Mcl-1 protein, a member of the Bcl-2 family,represents an attractive target for cancer treatment. The recent development of novelsmall molecule compounds has allowed Mcl-1-inhibitory therapy to proceed to clinicaltrials in cancer treatment. However, the possible adverse effects of either direct inhibitionof Mcl-1 or upregulation of Mcl-1S, proapoptotic isoform resulting from alternativesplicing of Mcl-1, remain unclear. Here, we investigated changes in Mcl-1S levelsduring cell cycle and the cell cycle-related functions of Mcl-1 isoforms to addressthe above-mentioned concerns. It was shown that an anti-mitotic agent monastrolcaused accumulation of Mcl-1S mRNA, although without increasing the protein level.In contrast, both mRNA and protein levels of Mcl-1S accrued during the premitoticstages of the normal cell cycle progression. Importantly, Mcl-1S was observed in thenuclear compartment and an overexpression of Mcl-1S, as well as knockdown ofMcl-1, accelerated the progression of cells into mitosis and resulted in DNA damageaccumulation. Surprisingly, a small molecule inhibitor of Mcl-1, BH3-mimetic S63845,did not affect the cell cycle progression or the amount of DNA damage. In general,upregulated Mcl-1S protein or genetically inhibited Mcl-1L were associated with the cellcycle perturbations and DNA damage accumulation in normal and cancer cells. At thesame time, BH3-mimetic to Mcl-1 did not affect the cell cycle progression, suggestingthat direct inhibition of Mcl-1 is devoid of cell-cycle related undesired effects.