Abstract
Previous reports have suggested that the ablation of the Period 2 gene (Per 2) leads to enhanced development of lymphoma and leukemia in mice. Employing immunoblot analyses, we have demonstrated that PER 2 is endogenously expressed in human breast epithelial cell lines but is not expressed or is expressed at significantly reduced level in human breast cancer cell lines. Expression of PER 2 in MCF-7 breast cancer cells significantly inhibited the growth of MCF-7 human breast cancer cells, and, when PER 2 was co-expressed with the Crytochrome 2 (Cry 2) gene, an even greater growth-inhibitory effect was observed. The inhibitory effect of PER 2 on breast cancer cells was also demonstrated by its suppression of the anchorage-independent growth of MCF-7 cells as evidenced by the reduced number and size of colonies. A corresponding blockade of MCF-7 cells in the G1 phase of the cell cycle was also observed in response to the expression of PER 2 alone or in combination with CRY 2. Expression of PER 2 also induced apoptosis of MCF-7 breast cancer cells as demonstrated by an increase in PARP [poly (ADP-ribose) polymerase] cleavage. Finally, our studies demonstrate that PER 2 expression in MCF-7 breast cancer cells is associated with a significant decrease in the expression of cyclin D1 and an up-regulation of p53 levels.
Highlights
IntroductionMost body functions follow a rhythmic pattern adjusted to a 24 h period (circadian rhythm), which is controlled by the circadian timing system [1,2]
In mammals, most body functions follow a rhythmic pattern adjusted to a 24 h period, which is controlled by the circadian timing system [1,2]
Expression of PER 2 in human breast epithelial and breast cancer cell lines Total cellular protein was isolated from two immortalized human breast epithelial cell lines (HME-tert and MCF10A), two ERα-positive human breast tumor cell lines (MCF-7 and T47D lines) and one ERα-negative human breast tumor cell lines (MDA-MB-231), and was examined by Western blot analysis using an antibody directed against the human PER 2 protein (Figure 1)
Summary
Most body functions follow a rhythmic pattern adjusted to a 24 h period (circadian rhythm), which is controlled by the circadian timing system [1,2]. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central rhythm generator located in the suprachiasmatic nucleus (SCN) of the hypothalamus [4]. The SCN pacemaker consists of multiple, autonomous single cell circadian oscillators, which are synchronized to fire rhythmically, generating a coordinated, rhythmic output in intact animals [5,6]. The cellular mechanism of circadian rhythmicity involves the regulation of three Period genes (Per 1–3) and two Chrytochrome genes (Cry and 2) [4]. Complexes of PER 2 and CRY 2 proteins enter the (page number not for citation purposes)
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