Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 67

transgenic mice. Similarly, increasing CK1d dosage shortens the endoge-

nous period of both S662 mutants but not wild type.
Taken together, these results lead to the proposal of the following model
regarding how CK1 acts on PER2 to regulate circadian period: CK1 phos-
phorylates the serine residues downstream of S662 on PER2 after S662 is
phosphorylated by a priming kinase. Phosphorylation in this region of
PER2 increases PER2 mRNA and thus protein, while CK1 likely phos-
phorylates some other site(s) that results in degradation of PER2. The net
effect of these two opposing processes determines the level of PER2 and
in turn sets circadian period. In wild-type background, the balance of these
opposing effects can be maintained, thus decreasing or increasing CK1d
gene dosage does not change the period. In the presence of S662Gmutation,
the S662 residue can no longer be phosphorylated by the priming kinase,
leading to hypophosphorylation of the downstream residues by CK1.
Therefore, the net effect of CK1 on mutant PER2 results in reduced
PER2 levels and shorter period. Decreasing CK1d

gene dosage partially sup-
presses the period shortening effect by reducing phosphorylation-mediated
PER2 degradation, whereas increasing CK1d gene dosage further shortens

period by enhancing phosphorylation-mediated PER2 degradation.

13. CUL1
A SNP in intron 3 of CUL1 is significantly associated with rheumatoid
arthritis (RA). 118 In lymphocytic cell lines, this SNP affects transcriptional
efficiency of CUL1 promoter activity. CUL1 is highly expressed in lym-
phoid tissues, and suppression of CUL1 inhibits IL-8 induction, which plays
an important role in migration of inflammatory cells into the affected area as
seen in RA. Therefore, this SNP in intron 3 of CUL1 could be affecting
susceptibility to RA by modulating expression levels of CUL1 . In another
independent study, this SNP, along with two other, constitutes a haplotype
that is significantly associated with RA and response to methotrexate treat-
ment, a commonly prescribed drug for RA patients. 119

14. b-TrCP

b-TrCP mutations have been implicated in cancer. Missense somatic
mutations in b-TrCP were identified in gastric cancers. 120 In tissues carrying

these mutations, b -catenin levels are increased with aberrant subcellular