Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 68

distribution, which may contribute to the development of gastric cancer.
Further evidence came from an association study demonstrating that a
9-bp deletion polymorphism in the 3 0 -UTR of b-TrCP correlates with
reduced risk of hepatocellular carcinoma (HCC). 121 Molecular analysis rev-
ealed that HCC tumor tissues with the deletion display reduced levels of
b -TrCP compared to those that do not carry the deletion. Because b -TrCP
is believed to be oncogenic, reduced b -TrCP levels associated with the dele-
tion variant could explain the reduced risk of HCC. Additionally, duplica-
tion of

b-TrCP gene is associated with split hand-split foot malformation. 122

15. DEC1
DEC1 was identified as one of the genes located in a commonly
deleted chromosomal region in a wide panel of esophageal squamous cell
carcinoma. 123 DEC1 transcript levels were significantly reduced in the

majority of esophageal cancer cell lines, while introducing DEC1 cDNA
into cancer cells that lack DEC1 expression significantly suppresses cell
growth. Consistently, a polymorphism in the promoter region of DEC1
(-249T/C) is significantly associated with the risk of squamous cell carci-
noma of the head and neck (SCCHN), and human subjects homozygous
for -249 C show significantly reduced susceptibility to SCCHN. 124
In silico analysis predicts that the -249 T to C change leads to a gain of a tran-
scription factor-binding site. Indeed, further functional analysis demon-
strated that the T-C change results in increased transcriptional activity at
DEC1 promoter and enhanced protein-DNA binding. In summary, these
results suggest that DEC1 functions as a tumor suppressor and genetic var-
iations in DEC1 could alter susceptibility to cancer.

16. DEC2
The first human mutation identified to cause a sleep homeostasis phe-
notype is in DEC2 . 125 Individuals carrying a proline to arginine mutation at
amino acid position 384 (P384R) of DEC2 have approximately 2-h shorter
sleep time per 24-h day compared to family members who do not carry the
mutation ( Fig. 3.2 ). Studies in cell culture demonstrated that the P384R
mutation results in attenuated DEC2 repressor activity of CLOCK/
BMAL1-driven transcription.
To validate that the P384R mutation is indeed causing the short-sleep
phenotype and not merely associated with the phenotype, BAC transgenic