Pathway
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
After translocation into the nucleus, the phosphorylated BMAL1:CLOCK heterodimer and, by inference, the BMAL1:NPAS2 heterodimer activate transcription by binding E-box elements (consensus: CANNTG) in the promoters of more than 2000 target genes (inferred from mouse homologs in Hatanaka et al. 2010, Guillaume et al. 2011) and recruiting coactivators such as CREB-binding protein (CREBBP) (inferred from mouse homologs in Garg et al. 2019), the histone methylase KMT2A (MLL1) and, presumably, components of the MLL1 complex (inferred from mouse homologs in Katada and Sassone-Corsi 2010). Transcriptional activation by BMAL1:CLOCK occurs during the day, thus genes regulated by BMAL1:CLOCK are diurnally expressed.
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Among the thousands of genes activated by BMAL1:CLOCK are the Cryptochrome genes (CRY1, CRY2) and the Period genes (PER1, PER2, PER3) that encode proteins that repress BMAL1:CLOCK activity, forming the primary loop of the circadian clock (reviewed in Cox and Takahashi 2019). BMAL1:CLOCK also activates the expression of Retinoid-related orphan receptor genes RORA, RORB, and RORC and the heme-binding nuclear receptor gene NR1D1 (REV-ERBA) that bind the same ROR responsive elements (RRE, RORE) in the promoters of the BMAL1, CLOCK, and NPAS2 genes. RORA, RORB, RORC activate expression; NR1D1 represses expression. The reciprocal regulation of BMAL1:CLOCK and RORA, RORB, RORC, NR1D1 forms the secondary loop of the circadian clock.
What the reference databases state
Statements
20 statements
20 statements · 1 reference database · Subject: Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes · Sources: Reactome
- BHLHE40 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- BMAL1 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- CIPC participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- CLOCK participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- CREBBP participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- CRTC1 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- CRY1 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- CRY2 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- DBP participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- KMT2A participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- NPAS2 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- NR1D1 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
Show the remaining 8
- PER1 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- PER2 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- PER3 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- RBM4 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- RORA participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- RORC participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- SIK1 participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only
- TFEB participates in Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genesProteinReactome R-HSA-9931510Inferred only