Ki-67 gene expression

Abstract

Ki-67 serves as a prominent cancer marker. We describe how expression of the MKI67 gene coding for Ki-67 is controlled during the cell cycle. MKI67 mRNA and Ki-67 protein are maximally expressed in G2 phase and mitosis. Expression is dependent on two CHR elements and one CDE site in the MKI67 promoter. DREAM transcriptional repressor complexes bind to both CHR sites and downregulate the expression in G0/G1 cells. Upregulation of MKI67 transcription coincides with binding of B-MYB-MuvB and FOXM1-MuvB complexes from S phase into G2/M. Importantly, binding of B-MYB to the two CHR elements correlates with loss of CHR-dependent MKI67 promoter activation in B-MYB-knockdown experiments. In knockout cell models, we find that DREAM/MuvB-dependent transcriptional control cooperates with the RB Retinoblastoma tumor suppressor. Furthermore, the p53 tumor suppressor indirectly downregulates transcription of the MKI67 gene. This repression by p53 requires p21/CDKN1A. These results are consistent with a model in which DREAM, B-MYB-MuvB, and FOXM1-MuvB together with RB cooperate in cell cycle-dependent transcription and in transcriptional repression following p53 activation. In conclusion, we present mechanisms how MKI67 gene expression followed by Ki-67 protein synthesis is controlled during the cell cycle and upon induction of DNA damage, as well as upon p53 activation.

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“…Two upregulated genes are conventional markers of mitotic cells, MKI67 and CCNB2 ; both gene products regulate the cell cycle transition at the G2/M stage. The KI-67 protein also maintains the mitotic chromosomes dispersed in the cytoplasm after nuclear envelope disassembly ( 58 ). Moreover, some key genes involved in cytokinesis were upregulated, which is the separation of chromosomes and cytoplasm, yielding two daughter cells ( 59 ).…”

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“…When MuvB is associated with B-Myb and/or FOXM1 it facilitates activation of the same cell cycle genes (reviewed in [ 29 ]). The cell cycle genes regulated by this system include MKI67 which has a promoter containing two CHR elements [ 31 ]. Although the DREAM pathway is characteristically activated after DNA damage through p53 upregulation of p21 transcription [ 32 ], hormonal (progesterone) activation of the DREAM pathway was recently shown in an ovarian cancer model [ 33 ].…”

“…Given that short courses of endocrine therapy that cause a decrease in Ki67 predict for long-term response to those agents [ 34 ], and Ki67 is a known DREAM regulated gene [ 31 ], it is possible that most if not all responses to endocrine therapy in ER+ breast cancers reflect a state of DREAM induced quiescence. This may be a reasonable hypothesis given that endocrine therapy is cytostatic with endocrine responsive tumours having the ability to recur once endocrine treatment is discontinued [ 35 ].…”

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“…There was a significant PAX6 mRNA downregulation when using the 1 µ M (FC = 0.7) and 5 µ M (FC = 0.6) concentrations in the at-RA treatment group MKI67 was used as a cell proliferation marker. MKI76 mRNA expression is the highest in the M Phase of the cells [11,12]; therefore, it could also be used as a proliferation marker.…”

“…MKI67 was used as a cell proliferation marker. MKI76 mRNA expression is the highest in the M Phase of the cells [ 11 , 12 ]; therefore, it could also be used as a proliferation marker.…”