p55Cdc proteins participate in activation and timing of ubiquitin ligation by APC/C. Labeling of the substrates with ubiquitin leads to degradation of the cell cycle proteins through the proteasome in mitosis. Consistent with the phase in which the protein functions p55Cdc mRNA is expressed during the cell cycle starting in S phase with a maximum in G(2)/M. We analyzed the human p55Cdc promoter responsible for this expression pattern and found with SIRF (Cell-Cycle Site-Regulating p55Cdc/Fizzy-Transcription) a novel element which downregulates transcription in a cell cycle-dependent manner. Activation of gene transcription is independent of the SIRF element and NF-Y. The nucleotide sequence of SIRF is essentially identical in human, rat, and mouse p55Cdc whereas other parts of the promoter are not conserved. SIRF requires its natural promoter context for its regulatory function. With a length of 44 nucleotides this element is unusually long and may require a large protein complex for its regulation. (C) 2004 Elsevier Inc. All rights reserved.