Abstract
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 novel small molecule compounds has allowed Mcl-1-inhibitory therapy to proceed to clinical trials in cancer treatment. However, the possible adverse effects of either direct inhibition of Mcl-1 or upregulation of Mcl-1S, proapoptotic isoform resulting from alternative splicing of Mcl-1, remain unclear. Here, we investigated changes in Mcl-1S levels during cell cycle and the cell cycle-related functions of Mcl-1 isoforms to address the above-mentioned concerns. It was shown that an anti-mitotic agent monastrol caused accumulation of Mcl-1S mRNA, although without increasing the protein level. In contrast, both mRNA and protein levels of Mcl-1S accrued during the premitotic stages of the normal cell cycle progression. Importantly, Mcl-1S was observed in the nuclear compartment and an overexpression of Mcl-1S, as well as knockdown of Mcl-1, accelerated the progression of cells into mitosis and resulted in DNA damage accumulation. 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 cell cycle perturbations and DNA damage accumulation in normal and cancer cells. At the same time, BH3-mimetic to Mcl-1 did not affect the cell cycle progression, suggesting that direct inhibition of Mcl-1 is devoid of cell-cycle related undesired effects.
Highlights
The Myeloid cell leukemia-1 (MCL1) gene was initially discovered in maturing human myeloid cells and revealed a significant sequence similarity to BCL2 (Kozopas et al, 1993)
The initiation of the DNA damage response occurred, no accumulation of Mcl-1S protein with molecular weight (MW) 32 kDa or mRNA was detected under these genotoxic conditions (Figures 1B,C)
It should be noted that the level of Mcl-1L mRNA and protein increased after 16 h incubation with 0.5 μM of doxorubicin
Summary
The Myeloid cell leukemia-1 (MCL1) gene was initially discovered in maturing human myeloid cells and revealed a significant sequence similarity to BCL2 (Kozopas et al, 1993). As one of the BCL2 family members, MCL1 possesses the Bcl-2 homology (BH) regions, whose composition determines the antiapoptotic or proapoptotic properties of the corresponding proteins (Letai et al, 2002). The presence of exon 1 causes retention of a large N-terminal region, which is identical to that of Mcl-1L (Senichkin et al, 2019). This N-terminus includes a mitochondrial targeting sequence (Perciavalle et al, 2012), putative nuclear localization signal (Ye et al, 2017) and PEST clusters (rich in proline, glutamic acid, serine, and threonine) (Kozopas et al, 1993). Mcl-1L can perform functions that are related to apoptosis and control nonapoptotic processes, such as the cell cycle (Senichkin et al, 2019)
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