and also has an effect on other oscillations throughout the body. For example, PER1 knockouts affect food entrainable oscillators and methamphetamine-sensitive circadian oscillators, whose periods are altered in the absence of PER1. In addition, mice with knockouts in both the PER1 and PER2 genes show no circadian rhythmicity. Phase shifts in PER1 neurons can be induced by a strong, brief light stimulus to the SCN of rats. This light exposure causes increases in PER1 mRNA, suggesting that the PER1 gene plays an important role in entrainment of the mammalian biological clock to the light-dark cycle. Feedback mechanism The PER1 mRNA is expressed in all cells, acting as a part of a transcription-translation negative feedback mechanism, which creates a cell autonomous molecular clock. PER1 transcription is regulated by protein interactions with its five E-box and one D-box elements in its promoter region. Heterodimer CLOCK-BMAL1 activates E-box elements present in the PER1 promoter, as well activating the E box promoters of other components of the molecular clock such as PER2, CRY1, and CRY2. The phase of PER1 mRNA expression varies between tissues, The transcript leaves the nucleus and is translated into a protein with PAS domains, which enable protein-protein interactions. PER1 and PER2 are phosphorylated by CK1ε, which leads to increased ubiquitylation and degradation. This phosphorylation is counteracted by PP1 phosphatase, resulting in a more gradual increase in phosphorylated PER, and an additional control over the period of the molecular clock. Phosphorylation of PER1 can also lead to masking of its leucine-rich nuclear localization sequence and thus impeded heterodimer import. PER interacts with other PER proteins as well as the E-box regulated, clock controlled proteins CRY1 and CRY2 to create a heterodimer which translocates into the nucleus. There it inhibits CLOCK-BMAL activation. PER1 is not necessary for the creation circadian rhythms, but homozygous PER1 mutants display a shortened period of mRNA expression. While PER1 must be mutated in conjunction with PER2 to result in arhythmiticity, the two translated PER proteins have been shown to have slightly different roles, as PER1 acts preferentially through interaction with other clock proteins. Clinical significance PER1 expression may have significant effects on the cell cycle. Cancer is often a result of unregulated cell growth and division, which can be controlled by circadian mechanisms. Therefore, a cell's circadian clock may play a large role in its likelihood of developing into a cancer cell. PER1 is a gene that