In mammals, several genes that encode members of the basic helix-loop helix (bHLH) PAS (PER-ARNT-SIM) transcription factor family have been shown to play a significant role in regulating circadian oscillations. Transactivation of CLOCK-induced genes is mediated via an E box enhancer (CACGTG) found upstream of target genes. CLOCK-ARNT 3 heterodimers bind to E box regulatory elements and stimulate gene transcription. CLOCK has been shown to transactivate the mammalian homolog of Drosophila PER. PER, in concert with the product of the mammalian timeless gene (TIM), negatively regulates its own transcription by blocking the activity of the CLOCK-BMAL 1 transactivation complex.