Regulation of cyclin B2 expression and cell cycle G2/m transition by menin.
Multiple endocrine neoplasia type 1 (MEN1) results from mutations in tumor suppressor gene Men1, which encodes nuclear protein menin. Menin up-regulates certain cyclin-dependent kinase inhibitors through increasing histone H3 lysine 4 (H3K4) methylation and inhibits G(0)/G(1) to S phase transition. However, little is known as to whether menin controls G(2)/M-phase transition, another important cell cycle checkpoint. Here, we show that menin expression delays G(2)/M phase transition and reduces expression of Ccnb2 (encoding cyclin B2). Menin associates with the promoter of Ccnb2 and reduces histone H3 acetylation, a positive chromatin marker for gene transcription, at the Ccnb2 locus. Moreover, Men1 ablation leads to an increase in cyclin B2 expression, histone H3 acetylation at the Ccnb2 locus, and G(2)/M transition. In contrast, knockdown of cyclin B2 diminishes the number of cells at M phase and reduces cell proliferation. Furthermore, menin interferes with binding of certain positive transcriptional regulators, such as nuclear factor Y (NF-Y), E2 factors (E2Fs), and histone acetyltransferase CREB (cAMP-response element-binding protein)-binding protein (CBP) to the Ccnb2 locus. Notably, MEN1 disease-related mutations, A242V and L22R, abrogate the ability of menin to repress cyclin B2 expression and G(2)/M transition. Both of the mutants fail to reduce the acetylated level of the Ccnb2 locus. Together, these results suggest that menin-mediated repression of cyclin B2 is crucial for inhibiting G(2)/M transition and cell proliferation through a previously unrecognized molecular mechanism for menin-induced suppression of MEN1 tumorigenesis.
Wu
Ting
T
Department of Biomedical Sciences, School of Life Science,Medical College, Xiamen University, Xiamen 361005, China.
Zhang
Xiuli
X
Huang
Xiaohua
X
Yang
Yuqing
Y
Hua
Xianxin
X
D000107:Acetylation; D000818:Animals; D049109:Cell Proliferation; D002469:Cell Separation; D056765:Cyclin B2 / Q000096:biosynthesis* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000737:chemistry; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D014158:Transcription, Genetic
D056765:Cyclin B2; D006657:Histones; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins
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