Eight core circadian genes have
been identified. They are: Casein kinase 1? (CK1?); Cryptochrome1 (Cry1)
and Chryptochrome2 (Cry2); Period1 (Per1),
Period2 (Per2), and Period3 (Per3); Clock;
and Bmal1. The three Per genes encode
PER-ARNT-SIM (PAS) domain proteins that function in the nucleus but do not
directly bind to DNA. The Clock and Bmal1 genes
encode basic-helix-loop-helix (bHLH)-PAS transcription factors. The levels of
mRNAs and proteins of these genes, except those of Clock and CK1?, oscillate
robustly during 24 hr circadian periods(1).

 

     
In this article, we will take the PER2 as an example of circadian gene
and its relationship with oncogenes and tumor suppressor genes based on recent
studies. In one study they first silenced PER2 expression in SCC15 human OSCC (oral squamous cell carcinoma) cells,
and, after PER2 silence, they found that the SCC15 cells not only change in
cell cycle progression, proliferation, and apoptosis but also greatly elevated
the cell metastasis, invasion, and tumorigenic ability in vivo. It is suggested
that PER2 also regulate the genes related to cancer cell metastasis, invasion,
and tumor angiogenesis.  The same study
showed evidences that PER2 silence in SCC15 (cell line name) cancer cells
upregulates expression of Ki-67, MDM2, c-Myc, Bcl-2, MMP2(a crucial gene and
can cause cancer invasion and metastasis) and VEGF mRNA and downregulates
expression of p53, Bax, and TIMP-2(is a major inhibitor of MMP2) mRNA. p53 is
an important tumor suppressor gene involved in DNA repair, cell cycle, tumor
angiogenesis, and other biological processes. MDM2 is the most vital molecule
regulating p53 concentration and activity and destroys p53 protein via
ubiquitination. PER2 downregulation decreased p53 mRNA expression and at the
same time increased MDM2 mRNA expression. From transcription level it has been
proved that PER2 knockdown can promote cell malignant transformation. Ki-67 and
c-Myc are vital genes that promote cell proliferation, and Bax and Bcl-2 are
essential genes that promote cell apoptosis and anti-apoptosis, respectively. The
same study proved that PER2 plays an important regulatory role in cell
proliferation and apoptosis. It is now considered that PER2 can regulate cell
cycle genes, sequentially, producing a close relationship with the occurrence
of cancers. This study further found that PER2 at the same time controls
numerous important downstream tumor-related genes of cell proliferation,
apoptosis, metastasis, invasion, and tumor angiogenesis, that is, Ki-67, MDM2,
c-Myc, p53, Bax, Bcl-2, MMP2, VEGF, and TIMP-2.(2)

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