Transcriptional Regulation: MYC, RB-E2F, and DREAM/MUVB
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P185-186
2025-11-02
62
Cell cycle entry and progression require specific genes to be expressed at certain times. When cell proliferation is triggered by growth conditions and cells leave quiescence, mitogen signaling leads to the activation of the MYC transcription factor.1 MYC has the capability to drive cell proliferation because it activates cyclin D and CDK4/6, and it plays an important role in cell growth because it upregulates ribosomal RNA and proteins, leading to increased ribosome biogenesis and translation. Indeed, experiments showed that when MYC is missing, cell growth and proliferation slow down, and cells arrest primarily in the G1 phase. MYC activity ensures that cells reach a certain size before entering the S phase and progressing through the cell cycle.
The two main cell cycle events—DNA synthesis and mitosis—take place after the cell passes the G1/S restriction point and is committed to cell cycle progression. Entry into the S phase requires the expression of genes required for DNA replication. These genes are distinct from the ones required for entry into mitosis. In general, there are two major waves of gene expression, one occurring just before entry into the S phase and a second wave occurring just before entry into mitosis (see Figs. 1 and 2). The periodic expression of mRNA produces the specific protein factors required for DNA replication and cell division. Once the S phase is completed and cells have passed through mitosis, many of these protein factors are ubiquitinated and degraded by the proteasome, thereby ensuring one-way progression through the S and M phases of the cell cycle.
Fig1. A MULTILAYERED NETWORK CONTROLS THE CELL CYCLE . Many proteins that carry out important functions during the cell cycle are encoded by genes that display a periodic expression pattern during the cell cycle. In G0 and early G1, DREAM and RB complexes repress the expression of cell cycle genes. In the late G1 and S phase, RB releases the activating E2F transcription factors that upregulate G1/S cell cycle genes encoding for important proteins in the process of DNA replication. When the S phase is completed, E2F7 and E2F8 will replace E2F1-3 and serve to repress the expression of the G1/S genes. In G2 and mitosis, B-MYB and FOXM1 transcription factors bind to the MuvB core and promote the expression of G2/M genes that encode important proteins for cell division. These transcription factors, as well as many other important cell cycle effectors, are controlled through phosphorylation by Cyclin-CDK complexes. Cyclin D-CDK4/6 complexes promote cell cycle entry and progression through the G1 phase. Cyclin E-CDK2 complexes stimulate S phase entry and progression, and Cyclin A-CDK2 complexes facilitate S phase completion. Cyclin A-CDK1 complexes promote G2 phase progression, and Cyclin B-CDK1 complexes regulate mitosis. These proteins are targets of an additional layer of cell cycle control that mediates their proteasomal degradation. APC/CCDH1 becomes activated in anaphase and promotes exit from mitosis, and ensures proper G1 phase progression. SCFSKP2 functions in the late G1 and early S phase, while SCFbetaTRCP and SCFFBXW7 are active throughout the S phase. SCFCyclin F stimulates mitosis entry, and APC/CCDC20 promotes progression through mitosis. Importantly, SCF, APC/C, and Cyclin-CDK complexes also regulate each other, and all these complexes contain effector proteins that are transcriptionally regulated by RB-E2F and MuvB complexes. This multilayered network ensures precise control of the cell cycle.
Fig2. TRANSCRIPTION CONTROL OF G1/S AND G2/M CELL CYCLE GENES. There are two major waves of gene expression, with one occurring just prior to entry into the S phase and a second wave just prior to entry into mitosis. The DREAM complex represses both early and late cell cycle gene expression during quiescence (red line). RB binds to the activating E2F transcription factors (E2F1–3) and blocks E2F-mediated activation of S phase genes. In the late G1 phase and S phase, the activating E2Fs dimerize with DP1 or DP2, bind to the promoters of genes required for DNA synthesis through E2F promoter elements, and promote their expression. During the late S phase, E2F7 and E2F8 will replace E2F1–3 and serve to repress the expression of the G1/S genes when DNA synthesis is completed. The B-MYB transcription factor binds to the MuvB core when p130, E2F4, and DP are released from the DREAM complex. The MMB complex recruits FOXM1 to promote the expression of genes in the late G2 phase and M phase.
Proliferating cells require the expression of specialized genes for the synthesis of DNA during the S phase and for cell division during mitosis. These cell cycle–dependent genes are not typically required for the survival of quiescent cells. The expression of more than 1000 cell cycle–dependent genes is nearly absent during quiescence in G0 cells. For the most part, the expression of these cell cycle–dependent genes is silenced by the trans-repressor complexes DREAM and RB-E2F. The DREAM complex is a multi-subunit protein com plex that binds to promoters of cell cycle–regulated genes and con tributes to their repression. The DREAM complex is comprised of the RB-like protein p130 (RBL2), E2F4 or E2F5, DP1 or DP2, and the 5-component MuvB complex containing LIN9, LIN37, LIN52, LIN54, and RBBP4. Whereas the DREAM complex contributes to the expression of both S phase– and M phase–specific genes, the RB protein specifically represses S phase–specific genes. RB binds to the activating E2F transcription factors (E2F1–E2F3) and blocks E2F-mediated activation of S phase genes. S and M phase genes possess distinct promoter elements that mediate the binding of RB-E2F and DREAM complexes. E2F promoter elements contain the canonical DNA sequence TTTCGCGC and specifically mediate binding of E2F transcription factors in S phase genes. In contrast, M phase genes possess cell cycle genes homology region (CHR) promoter elements that comprise the canonical DNA sequence TTTGAA and specifically mediate the binding of the MuvB complex.
When a quiescent cell is stimulated to enter the cell cycle, it begins to express cyclin D that binds to CDK4 or CDK6 and is capable of monophosphorylating RB. In the late G1 phase, Cyclin E–CDK2 complexes multi-phosphorylate the monophosphorylated RB, leading to the release of the activating E2F transcription factors.8 The activating E2Fs dimerize with DP1 or DP2, bind to the promoters of genes required for DNA synthesis through E2F promoter elements, and promote their expression during the late G1 phase and S phase. These G1/S genes encode many of the factors required for DNA replication. During the late S phase, E2F7 and E2F8, which are E2F targets themselves, will replace E2F1–E2F3 and serve to repress the expression of the G1/S phase genes when DNA synthesis is completed.
Cyclin D–CDK4/6 and cyclin E–CDK2 are also capable of phosphorylating p130, thereby enabling the release of p130 from the DREAM complex. The B-MYB (MYBL2) transcription factor is encoded by a G1/S gene and binds to the MuvB core when p130, E2F4, and DP are released from the DREAM complex. The newly formed MMB (B-MYB–MuvB) complex does not contain any E2F transcription factor and thus binds exclusively to genes that possess CHR promoter elements. These genes are highly expressed in late G2 phase and M phase and encode for proteins that carry out essential functions in mitosis. The MMB complex recruits FOXM1, a third transcription factor, to promote the expression of these G2/M genes. Notably, FOXM1 is a G2/M gene itself, and together with the important role of FOXM1 in promoting the expression of G2/M genes, FOXM1 has emerged as one of the most robust biomarkers for stratifying high-risk and low-risk cancers. The B-MYB and FOXM1 fac tors are ubiquitinated and destroyed by the proteasome during late mitosis, resulting in a decrease in expression of the G2/M genes when a cell exits mitosis. Therefore the DREAM complex represses all cell cycle genes during quiescence, with the G1/S cell cycle genes being activated by E2F1–E2F3 and the G2/M late cell cycle genes being activated by B-MYB–MuvB–FOXM1.
Together, proliferation signals will enable MYC-dependent gene expression that contributes to the growth in the size of the cell, whereas the E2F and B-MYB/FOXM1-dependent gene expressions induce genes required for DNA replication during the S phase and cell division during mitosis. Given the strong link between the expression of cell cycle-regulated genes and cell proliferation, cell cycle genes have prognostic value for stratifying cancers because malignancy correlates with the number of proliferating cells in a tumor.
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