has been shown to interact with: ARNTL (also known as BMAL1). Like Clock, Npas2 mRNA cycles with a similar phase to that of Bmal1, with both peaking 8 hours before the peak of Per2 mRNA expression. This is consistent with the observation that NPAS2 forms a heterodimer with BMAL1 to drive Per2 expression. EP300. NPAS2 and EP300 interact in a time-dependent, synchronized manner. EP300 is recruited to NPAS2 as a coactivator of clock gene expression. Retinoic acid receptor alpha (RARα) and retinoid X receptor alpha (RXRα). In peripheral clocks, RARα and RXRα interact with NPAS2 by inhibiting the NPAS2:BMAL1 heterodimer-mediated expression of clock genes. This interaction depends upon humoral signaling by retinoic acid and serves to phase-shift the clock. Small heterodimer partner (SHP). In the liver circadian clock, NPAS2 and SHP engage in a TTFL: NPAS2 controls the circadian rhythms of SHP by rhythmically binding to its promoter, while SHP inhibits transcription of Npas2 when present. Clinical significance Npas2 genotypes can be determined through tissue samples from which genomic DNA is extracted and assayed. The assay is performed under PCR conditions and can be used to determine specific mutations and polymorphisms. Polymorphisms and tumorigenesis Mounting evidence suggests that the NPAS2 protein and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. These findings provide evidence suggesting a possible role for the circadian Npas2 gene in cancer prognosis. These results have been confirmed in both breast and colorectal cancers. NPAS2 and mood disorders Current research has revealed an association between seasonal affective disorder (SAD) and general mood disorder related to NPAS2, ARNTL, and CLOCK polymorphisms. These genes may influence seasonal variations through metabolic factors such as body weight and appetite. Associated with a connection to mood disorders, NPAS2 has been found to be involved with dopamine degradation. This was first suggested by the observation that the clock components BMAL1 and NPAS2 transcriptionally activated a luciferase reporter driven by the murine monoamine oxidase A (Maoa) promoter in a circadian fashion. This suggested that these two clock components (BMAL1 and NPAS2) directly regulated Maoa transcription. Subsequent findings discovered positive transcriptional regulation of BMAL1/NPAS2 by PER2. In mice lacking PER2, both Maoa mRNA and MAOA protein levels were decreased. Therefore, dopamine degradation was reduced, and