Associated Risk Nuclear Bodies

RESEARCH HIGHLIGHTS

CIRCADIAN RHYTHMS TUMORIGENESIS Clocking on Nuclear bodies

Tumorigenesis that is driven by loss phospho-AKT (pAKT) localiza- of the tumour suppressor PTEN tion was an inherent feature of is known to activate the proto- Pml loss, Pandolfi and colleagues oncogene AKT in many human can- looked at the AKT status of Pml+/+ cers. Activation of cytoplasmic AKT and Pml–/– mouse embryonic has been thought to be the most rel- fibroblasts (MEFs). After the addi- evant. However, Pier Paolo Pandolfi tion of serum to the cell culture, and colleagues now show that AKT activation — especially in Women who work at night have an increased risk of additional deficiency of the tumour the nucleus — was sustained in developing breast or colon cancer, which could be evidence suppressor PML — which forms Pml–/– MEFs. If Pml was transduced that disruption of our circadian rhythm upsets more than just dynamic intranuclear structures into Pml–/– cells, AKT activation our sleep patterns. The genes that regulate the circadian clock (nuclear bodies) that are involved in decreased. These findings were in mammals have recently been identified, and Sigal Gery and apoptosis, proliferation and senes- confirmed by confocal laser scan- colleagues now show that one of these genes, period 1 (PER1), cence — leads to an increase in the ning microscopy. might function as a tumour-suppressor gene. nuclear localization of AKT, which So, does Pml loss increase the Given the established link between circadian rhythms and accelerates tumorigenesis. function of nuclear pAKT? The the DNA-damage response, the authors investigated the First the authors studied the forkhead transcription factor response to ionizing radiation (IR) of colorectal cancer cell effect of Pml loss on AKT activa- FOXO3a is a nuclear target of lines that overexpress PER1. The authors showed that tion in Pten+/– mice. AKT activa- pAKT, and phosphorylation of overexpression of PER1 induced high expression levels of p53 tion increased by 50% in normal FOXO3a leads to its inactivation that were only slightly increased after treatment with IR. colon and prostate cells, particu- and export from the nucleus. Despite p53 expression, these cells did not have increased larly in the nuclear compartment, Decreased nuclear FOXO3a was expression of p21, the cyclin-dependent-kinase inhibitor that and led to the development of seen after serum stimulation in mediates p53-induced cell-cycle arrest after DNA damage. colon and prostate cancers. To Pml–/– MEFs compared with Pml+/+ This is because, after IR, PER1 overexpression results in the investigate whether the change in MEFs. In addition, the FOXO3a increased expression of the oncoprotein MYC, which is known to inhibit p21 expression and induce apoptosis. Therefore, cells that expressed PER1 were less able to arrest in G2/M and POPULATION GENETICS had higher rates of apoptosis than control cells. Given that PER1 seems to be important for the cellular response to IR, does it interact with other proteins that regulate this pathway? Co-immunoprecipitation experiments Associated risk showed that PER1 can interact with the DNA-damage- response kinase, ataxia telangiectasia mutated (ATM), and the Family history and ethnicity are This could be because the allele itself checkpoint protein CHK2. The authors propose that PER1 known risk factors for prostate confers risk, or because it is close to the might facilitate the activation of ATM or might function as an cancer, but little is known about locus that does and most individuals adaptor protein that recruits other proteins that are required the genetic factors behind them. who carry the microsatellite allele for the ATM-mediated response to DNA damage. Amundadottir et al. have now shown also carry the risk allele. This would Overexpression of PER1 in various cancer cell lines inhibited that a common allele is associated be the case if there had been little clonogenic growth as well as anchorage-independent growth, with prostate cancer, and that it is recombination between the two loci which further indicates that PER1 might function as a tumour more common in men of African since the risk allele arose by mutation. suppressor. So the authors investigated whether PER1 descent, who are at greater risk Significantly, the authors found that expression is altered in human cancer. Reverse transcriptase- of prostate cancer, than in men of the DG8S737–8, which also increases the severity of prostate cancer, was PCR analyses showed that 70% of human non-small-cell lung European descent. Variation at microsatellite loci might more common in men of African descent cancer samples and 46% of human breast cancer samples had have functional consequences, and and was also closely associated with reduced expression levels of PER1 compared with controls. can also be used to search for regions prostate cancer risk in this population. These results further increase our preliminary of the genome that are associated with First, this could explain why prostate understanding of how the circadian clock regulates pathways disease risk. The authors genotyped cancer is more common and more that are crucial for the suppression of malignant growth. European men with prostate cancer severe in men of African descent; and Nicola McCarthy and found that one particular second, it shows that the area of the microsatellite allele, DG8S737–8, on chromosome in which the risk factor ORIGINAL RESEARCH PAPER Gery, S. et al. The circadian gene Per1 plays an chromosome 8q24 is associated with lies is very close to the microsatellite, important role in cell growth and DNA damage control in human cancer cells. Mol. disease risk. as all but the closest associations would Cell 22 375–382 (2006)