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, 42 (12), 836-839

Involvement of RUNX and BRD Family Members in Restriction Point

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Involvement of RUNX and BRD Family Members in Restriction Point

Jung-Won Lee et al. Mol Cells.

Abstract

A tumor is an abnormal mass of tissue that arises when cells divide more than they should or do not die when they should. The cellular decision regarding whether to undergo division or death is made at the restriction (R)-point. Consistent with this, an increasingly large body of evidence indicates that deregulation of the R-point decision-making machinery accompanies the formation of most tumors. Although the R-point decision is literally a matter of life and death for the cell, and thus critical for the health of the organism, it remains unclear how a cell chooses its own fate. Recent work demonstrated that the R-point constitutes a novel oncogene surveillance mechanism operated by R-point-associated complexes of which RUNX3 and BRD2 are the core factors (Rpa-RX3 complexes). Here, we show that not only RUNX3 and BRD2, but also other members of the RUNX and BRD families (RUNX1, RUNX2, BRD3, and BRD4), are involved in R-point regulation.

Keywords: BRD; RUNX; restriction point.

Conflict of interest statement

Disclosure

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. Transient interaction between RUNXs and BRDs early after serum stimulation
(A) Amino acid sequence similarities between RUNX1, RUNX2, and RUNX3. Conserved lysines (K) recognized by bromodomain 1 (BD1) of BRD2 are indicated. (B) Schematic of wild-type (BRD2-WT) and mutant BRD2. BD1 interacts with RUNX3 acetylated at K-94 and K-171; BD2 interacts with acetylated histones H4K4-ac, H4K12-ac, and H3K14-ac. Y113 and Y386 are essential tyrosines in BD1 and BD2, respectively. Y > F indicates a tyrosine-to-phenylalanine mutation. (C) HEK293 cells were transfected with Myc-RUNX1, FLAG-BRD2-WT, and FLAG-BRD2 mutant described in Figure 1B. Cells were serum-starved for 24 h, and then stimulated with 10% serum. Cells were harvested 2 h later, and the interactions of the proteins were measured by co-IP and IB, as indicated. (D) HEK293 cells were transfected with Myc-RUNX2, FLAG-BRD2-WT, and FLAG-BRD2 mutant, and then treated as described in Figure 1C. Protein–protein interactions were measured by IP and IB as indicated. (E) HEK293 cells were transfected with Myc-RUNX1, Myc-RUNX2, or Myc-RUNX3; serum-starved for 24 h; and then stimulated with 10% serum. Cells were harvested at the indicated time points, and the levels of the indicated proteins and their time-dependent interactions were measured by co-IP and IB. (F) HEK293 cells were transfected with Myc-KRASG12D with Myc-RUNX1, Myc-RUNX2, or Myc-RUNX3, and treated as described in Figure 1E. The levels of the indicated proteins and their time-dependent interactions were measured by co-IP and IB.
Fig. 2
Fig. 2. The predicted sequential molecular events for the R-point decision
Upon mitogenic stimulation, p300 associates with RUNXs and acetylates RUNXs and histones. One hour after mitogenic stimulation, BRDs bind both acetylated RUNXs and acetylated histone through their bromodomains. Subsequently, SWI/SNF, MLL1/5, and TFIID bind to the C-terminal region of BRDs. The large complex of which RUNXs are the core was named Rpa-RX-AC. When the RAS-MEK signal is downregulated, the Cyclin D1–HDAC4–PRC1 complex binds to Rpa-RX-AC, yielding Rpa-RX-TR. The Cyclin D1–HDAC4–PRC1 complex dissociates from Rpa-RX-TR to form Rpa-RX-RE. The cell cycle then progresses toward S-phase. If K-RAS is constitutively activated, the RAS-MEK signal is not downregulated, and Rpa-RX-AC is maintained for a long time; consequently, the cell cycle arrests or the cell undergoes apoptosis.

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