Bmall

Recent experimental studies have uncovered a direct link between the cell cycle and circadian rhythms. Thus, the circadian clock protein BMALl induces the expression of the gene Weel, which codes for the protein kinase that inactivates through phosphorylation the kinase cdkl that controls the G2/M transition [149]. This link allows the coupling of cell division to the circadian clock and explains how the latter may entrain the cell cycle clock in a variety of cell types. 

Travnickova-Bendova Z, Cermakian N, Reppert SM, Sassone-Corsi P 2002 Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/ BMALl activity. Proc Natl Acad Sci USA 99 7728-7733... 

Loros Certainly, but if you get rid of the PAS domains in White Collar 1, BMALl is still going to come up in a sequence-based homology search like BLAST. 

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). 

Schibkr Absolutely. The ROR is not under the direct control of REV-ERBa, even though it has a similar phase as BMALl. 

Ishida With respect to Ufespan, work by Paul Shaw on cjfi mutant flies showed that they became very sensitive to desiccation and sleep stress (Shaw et al 2002). cjfi flies died early after sleep deprivation. So the molecular mechanism of lifespan might be related to that of the circadian system. But another possibility is that BMALl and CLOCK regulate many other output factors, such as stress-sensitive proteins. 

Although a substantial body of evidence indicates that the functions of DBT and SGG depend on PER and TIM phosphorylation respectively, these may not be the only substrates in the Drosophila clock. For example, in mammals it was recently found that casein kinase 1 phosphorylates CRY and BMALl (the orthologue of CYC) in addition to PER (see below) (Eide et al 2002). 

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. 

Newtonians, but its use is justifiable since it may be rigorously shown to be that apparent viscosity which must be used in order to define the pressure drop precisely in laminar flow. The difference between these two types of apparent viscosity is Bmall for the work in question and, to avoid confusion, has not been considered in this presentation. 

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