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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

The protein encoded by this gene is a basic-helix-loop-helix PAS (bHLH-PAS) domain containing protein that forms a heterodimer with a second bHLH-PAS protein, Clock, or its ortholog, Npas2[1]. This complex binds to E-box response elements[2] in promoter regions of many genes including those encoding the Period (Per1, Per2, Per3)[3] and Cryptochrome (Cry1 and Cry2)[4] proteins. These repressor proteins are translated, and bind in a complex with casein kinase 1ε (Csnk1e) and 1δ (Csnk1d)[5][6]. Next, the entire complex translocates to the nucleus, where it interacts with the Arntl/Clock heterodimer to inhibit its transactivation (Fig. 1). This hypothesis is supported by the observation that point mutants in the Arntl or Clock render them resistant to interaction and repression by Cryptochromes [7]. Transcription of Period and Cryptochrome genes, therefore, is inhibited, the protein levels of Period and Cryptochrome genes drop, and eventually repression is relieved to allow their transcription to build up again. This process occurs with a period length of approximately 24 hours.

References
  1. Debruyne JP. Oscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system. J. Genet., 87(5):437-46. (PMID 19147932)
  2. Hogenesch JB et al. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl. Acad. Sci. U.S.A., 95(10):5474-9. (PMID 9576906)
  3. Gekakis N et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science, 280(5369):1564-9. (PMID 9616112)
  4. Kume K et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell, 98(2):193-205. (PMID 10428031)
  1. Lowrey PL et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science, 288(5465):483-92. (PMID 10775102)
  2. Lee C et al. Posttranslational mechanisms regulate the mammalian circadian clock. Cell, 107(7):855-67. (PMID 11779462)
  3. Sato TK et al. Feedback repression is required for mammalian circadian clock function. Nat. Genet., 38(3):312-9. (PMID 16474406)
Figures
FIGURE 1 Simplified Mammalian Clockwork Model
The bHLH-PAS transcription factors CLOCK and ARNTL heterodimerize, and bind E-box elements to drive expression of the mPer1, mPer2 and mCry1 and mCry2 clock genes. The PER (P) and CRY (Cr) proteins form a complex along with CKI δ/ε (CKI) and translocate into the nucleus where they bind CLOCK:BMAL1 to inhibit transcription (-), completing the essential negative feedback loop. Posttranslational modification (black lollipops) of several of these components appears to help maintain ~24 hour rhythmicity. CLOCK:ARNTL heterodimers also drive expression of Ror’s (Ro) and Rev-erb α/β (Re), which are transcriptional activators (+) or repressors (-), respectively, that drive cyclical ARTNL expression via Ror elements within the ARNTL promoter, in a secondary feedback loop that appears to stabilize rhythms. Clock controlled genes (CCG’s) are output genes directly regulated by this central clockwork. This Figure is modified from DeBruyne (2008) J Genet. 87(5):437-46.
This figure is from a publication by the authors of this article. Please click here to view the publication's entry in Pubmed (PMID 19147932).