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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.

SUBMITTER: Uxa S

PROVIDER: S-EPMC8629999 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Ki-67 gene expression.

Uxa Sigrid S Castillo-Binder Paola P Kohler Robin R Stangner Konstanze K Müller Gerd A GA Engeland Kurt K

Cell death and differentiation 20210628 12

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 ...[more]

PMID: 34183782

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Project description:BackgroundIntrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver cancer with dismal outcome, high Ki-67 expression is associated with active progression and poor prognosis of iCCA, the application of MRE in the prediction of iCCA Ki-67 expression has not yet been investigated until now. We aimed to evaluate the value of magnetic resonance elastography (MRE) in assessing Ki-67 expression for iCCA.ResultsIn the whole cohort, 97 patients (57 high Ki-67 and 40 low Ki-67; 58 males, 39 females; mean age, 58.89 years, ranges 36-70 years) were included. At the multivariate analysis, tumor stiffness (odds ratio (OR) = 1.669 [95% CI: 1.307-2.131], p < 0.001) and tumor apparent diffusion coefficient (ADC) (OR = 0.030 [95% CI: 0.002, 0.476], p = 0.013) were independent significant variables associated with Ki-67. Areas under the curve of tumor stiffness for the identification of high Ki-67 were 0.796 (95% CI 0.702, 0.871). Tumor stiffness was moderately correlated with Ki-67 level (r = 0.593, p < 0.001). When both predictive variables of tumor stiffness and ADC were integrated, the best performance was achieved with area under the curve values of 0.864 (95% CI 0.780-0.926).ConclusionMRE-based tumor stiffness correlated with Ki-67 in iCCA and could be investigated as a potential prognostic biomarker. The combined model incorporating both tumor stiffness and ADC increased the predictive performance.Critical relevance statementMRE-based tumor stiffness might be a surrogate imaging biomarker to predict Ki-67 expression in intrahepatic cholangiocarcinoma patients, reflecting tumor cellular proliferation. The combined model incorporating both tumor stiffness and apparent diffusion coefficient increased the predictive performance.Key points• MRE-based tumor stiffness shows a significant correlation with Ki-67. • The combined model incorporating tumor stiffness and apparent diffusion coefficient demonstrated an optimized predictive performance for Ki-67 expression. • MRE-based tumor stiffness could be investigated as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.

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Ki-67 gene expression.

Publications

Ki-67 gene expression.

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