The Role of MKI67 in the Regulation of 60S Pre-ribosome Nucleolar Export, Transcripts, Energy Supply, and Apoptosis

MKI67 (Ki67) is expressed exclusively in proliferating cells in human tissues, rendering it as a valuable diagnostic marker for cancer. However, the function of this protein in cells remains unclear. In this study, we present the findings on the regulatory functions of MKI67 in conjunction with its partner proteins GNL2 and MDN1, which are involved in pre-ribosome processing, as well as the regulatory functions in its absence. In proliferating HEK293T cells, MKI67 binds contiguously to the chromatin in conjunction with GNL2 and MDN1, localizing most densely to the nucleolar periphery to regulate 60S pre-ribosome export. On the other hand, RNA-seq analysis reveals that these three proteins can independently regulate many target transcripts, but they often share their target transcripts, yet often regulate them at different expression levels. MDN1 depletion strongly downregulates RNA gene transcripts involved in ribosome biogenesis and splicing. In contrast, MKI67 depletion strongly upregulates transcripts of protein-coding genes, including synapse-specific proteins and the mitosis-related protein NEK7. Furthermore, MKI67 depletion coordinately up- or down-regulates the levels of transcripts of several pathways, thereby enabling MKI67-depleted cells to adapt to less active metabolic states. The underlying mechanism by which MKI67 depletion upregulates transcripts appears to involve attenuation of transcript levels in cooperation with mRNA degradation systems, as evidenced by analysis of NEK7 and UNC13A translations. In conclusion, the present results indicate that MKI67 contributes to proliferation via nucleolar export of 60S pre-ribosome particles and high energy supply. Conversely, its absence leads the cells to adapt to the senescent and differentiated conditions.