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.
Highlights
The Ki-67 protein is a prominent proliferation marker used in pathology [1, 2]
C Flow cytometry analyses of propidium iodide (PI) staining of hTERT-BJ cells analyzed in A and B
DREAM, E2F, and FOXM1/B-MYB/MuvB complex components bind to the MKI67 promoter in vivo and in vitro After identifying the regulatory sites in the MKI67 gene, we investigated protein binding to the promoter
Summary
The Ki-67 protein is a prominent proliferation marker used in pathology [1, 2]. Ki-67 was first identified as an antigen for a monoclonal antibody detected in the nuclei of proliferating cells [1, 3]. The function of this protein remained obscure, even after antibodies directed against Ki-67 were already established tools in cancer diagnostics. With the establishment of the Ki-67 labeling index, Ki-67 has developed into a standard in diagnosis and prognosis assessment of cancer patients [2]. Complemented by cancer tissue-specific markers, Ki-67 serves as a general indicator for diagnosis and prognosis. The diagnostic procedure for breast cancer with assessment of estrogen receptor, HER2, progesterone receptor, and Ki-67 represents one such example [5]
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