Negative Regulation: Rb, p53, and p21
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Retinoblastoma protein, p53, and p21 are the cell cycle's best-understood negative regulators, acting mainly at the G1 checkpoint to block progression until conditions are satisfied.
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Retinoblastoma protein binds transcription factor E2F, blocking the genes a cell needs to enter S phase.
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A negative regulator's activity halts the cycle — losing it, not gaining it, allows uncontrolled division.