Bmall transcription activators

Lastly, there are phosphorylation events in both Drosophila and mammals for which the function and associated kinases have not been identified as mentioned above, the kinase(s) that rhythmically phosphorylates Drosophila and mammalian CLK is not yet known, and it will be important to determine whether phosphorylation of CLK influences its transcriptional activity or its ability to bind to DNA. Although CKle modifies mammalian CRYl, CRY2 and BMALl in vitro (Eide et al 2002), and CKld will similarly phosphorylate some mammalian PER proteins (Camacho et al 2001), none of these activities have been securely established in vivo. 

The mammalian molecular oscillator, similar to that in Drosophila and Neurospora, is composed of two interconnected feedback loops, one within the negative limb and one within the positive limb. The members of the positive limb (CLOCK and BMALl) activate transcription of the genes encoding the negative limb components (cryptochromes and period proteins). PER and CRY proteins then form heterotypic protein complexes that are translocated into the nucleus, and once these complexes reach a critical threshold level, they suppress the activity of CLOCK and BMALL As a consequence, the concentration of CRY and PER proteins falls below the threshold required for autorepression, and a new cycle of CryjPer transcription can initiate (for review, see Reppert Weaver 2002). 

CRY and PER proteins not only repress the activity of their own genes, but they also stimulate the expression of BMALl and CLOCK. How can the CRY and PER repressors activate the transcription of these positive hmb components The most likely scenario would imply a hitherto unknown repressor whose gene is under the negative control of CRYs and PERs. 

Subsequent studies revealed that the transcription of Rev-erba, is regulated by essentially the same mechanisms as those of Per and Cry genes it is activated by BMALl and CLOCK and repressed by PER and CRY. Therefore, REV-ERBa directly connects two antiphasic feedback loops within the positive and negative limbs of the oscillator (Fig. 1). 

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