Cryptochrome deletion in p53 mutant mice enhances apoptotic and anti-tumorigenic responses to UV damage at the transcriptome level

Cavga, Ayşe Derya; Tardu, Mehmet; Korkmaz, Tuba; Keskin, Özlem; Öztürk, Nuri; Gürsoy, Attila; Kavaklı, İbrahim Halil

doi:10.1007/s10142-019-00680-5

Cited by 10 publications

(6 citation statements)

References 58 publications

(84 reference statements)

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“…Several attempts have been made to correlate clock gene polymorphisms or expression levels in either cancer cell lines or tissues from various cancers to determine whether clock gene mutations ( 62 ) or levels of expression ( 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ) play a role in initiation or progression of cancer and susceptibility of cancer to a particular drug and a particular time of day for delivery of the drug (chronochemotherapy). The effects of clock gene polymorphism are small, and both predisposing and protective mutations were observed in comparable levels, and thus it is unclear whether these associations have a pathogenic role in the observed phenotypes ( 33 ).…”

Section: Circadian Clock–carcinogenesismentioning

confidence: 99%

Circadian clock, carcinogenesis, chronochemotherapy connections

Yang

Lindsey-Boltz

Vaughn

et al. 2021

Journal of Biological Chemistry

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The circadian clock controls the expression of nearly 50% of protein coding genes in mice and most likely in humans as well. Therefore, disruption of the circadian clock is presumed to have serious pathological effects including cancer. However, epidemiological studies on individuals with circadian disruption because of night shift or rotating shift work have produced contradictory data not conducive to scientific consensus as to whether circadian disruption increases the incidence of breast, ovarian, prostate, or colorectal cancers. Similarly, genetically engineered mice with clock disruption do not exhibit spontaneous or radiation-induced cancers at higher incidence than wild-type controls. Because many cellular functions including the cell cycle and cell division are, at least in part, controlled by the molecular clock components (CLOCK, BMAL1, CRYs, PERs), it has also been expected that appropriate timing of chemotherapy may increase the efficacy of chemotherapeutic drugs and ameliorate their side effect. However, empirical attempts at chronochemotherapy have not produced beneficial outcomes. Using mice without and with human tumor xenografts, sites of DNA damage and repair following treatment with the anticancer drug cisplatin have been mapped genome-wide at single nucleotide resolution and as a function of circadian time. The data indicate that mechanism-based studies such as these may provide information necessary for devising rational chronochemotherapy regimens.

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Section: Circadian Clock–carcinogenesismentioning

confidence: 99%

Circadian clock, carcinogenesis, chronochemotherapy connections

Yang

Lindsey-Boltz

Vaughn

et al. 2021

Journal of Biological Chemistry

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“…And this study preliminarily investigated that miR-29a affects the invasion and migration of residual A549 cells after radiation by regulating the interaction between PER1 and LAMR1. The Per1 gene is located at 17p13.1p12 and encodes a protein about 1290 amino acids long with a molecular mass of 136 kD, whose protein is mainly localized in the nucleus.Per1 is an oncogene that regulates many key cell cycle proteins downstream, leading to alterations in cell cycle and proliferation that are closely associated with cancer development [15]. In another study on glioma, it was found that down-regulation of Per1 gene expression reduced the sensitivity of U343 glioma cells to X-ray irradiation and decreased glioma cell apoptosis [16].…”

Section: Discussionmentioning

confidence: 99%

miR-29a dynamically regulates the invasion and migration ability of residual A549 cells after radiation by inhibiting PER1-LAMR1 interaction

Chi¹,

Zuo²,

Chen³

et al. 2022

Preprint

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Current studies have shown that the recent rhythm gene Per1 (Period 1) is expressed down-regulated in various malignancies and plays an important role in tumorigenesis and progression. However, the biological function and mechanism of action of Per1 in non-small cell lung cancer (NSCLC) is not clear. In this study, we demonstrated that miR-29a could inhibit the interaction between Per1 and laminin receptor 1 (LAMR1), and the invasion and migration ability of A549 cells after 8Gy X-ray irradiation showed dynamic changes, firstly weakened or enhanced. The inhibition or overexpression of miR-29a, Per1, and LAMR1 was performed to investigate their roles and mechanisms in vitro. We found that miR-29a was able to significantly inhibit the expression of Per1 gene, while the invasion and migration ability of residual A549 cells after radiation showed a dynamic change of diminished and then enhanced. Further study revealed that the reason for this dynamic change might be that miR-29a affected the binding of laminin (LN) to LAMR1 through the interaction of Per1 and LAMR1. In summary, our study demonstrates for the first time that it may be miR-29a that inhibits the interaction between Per1 and LAMR1, which causes a dynamic change in the invasive migration ability of residual A549 cells after radiation by competitively binding to LN, and that Per1 may serve as a valuable biological target for good or bad prognosis of NSCLC.

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“…Additionally, as previously shown, deletion of Cry genes in p53 -/in C57BL/6J background enhances the lifespan of the animals by protecting animals from cancer death 35 . A recent transcriptomic study revealed that differential regulation of nuclear factor kappa B (NF-κB) regulation may increase survival rate 36 . We wished to test M47 on p53 -/animals to see whether it delays cancer death and change the lifespan in cancer prone p53 -/in C57BL/6J mice.…”

Section: Effect Of M47 On the Lifespan Of P53 -/Micementioning

confidence: 99%

Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice

Gül

Akyel

Gul

et al. 2021

Preprint

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Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous level of the CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis is unknown. Here, we discovered a molecule that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The small molecule, called M47, selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and the period of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 enhanced degradation rate of the CRY1 level in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced cisplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Finally, systemic repetitive administration of M47 increased the median lifespan of p53-/- mice by ~25%. Collectively our data suggest that M47 is a very promising molecule to treat forms of cancer depending on the p53 mutation.

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Cryptochrome deletion in p53 mutant mice enhances apoptotic and anti-tumorigenic responses to UV damage at the transcriptome level

Cited by 10 publications

References 58 publications

Circadian clock, carcinogenesis, chronochemotherapy connections

Circadian clock, carcinogenesis, chronochemotherapy connections

miR-29a dynamically regulates the invasion and migration ability of residual A549 cells after radiation by inhibiting PER1-LAMR1 interaction

Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice

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