| DNA is the carrier of genetic information.Maintaining the integrity and stability of the genome is very important for cell’s proliferation and function.DNA is under attack from the internal or external agents, such as ROS, ionizing radiation and environmental mutagens. DNA damage includs double-stranded breaks(DSBs), single strand breaks, DNA insertion, deletion, nucleotide bases modifications, and chromosome translocation, with DSBs being hazardous. On the other hand, many anti-cancer drugs kill rapidly growing tumor cells by causing DNA damage. For example, Doxorubicin, an anthracycline-based antitumor drug, is potent against many types of tumor cells by inserting into DBS and single strand.DNA Damage activates multiple signaling pathways to cause cell cycle arrest, cell apoptosis, or senescence.PI3K-like protein kinase family(PIKK) act at the core step of DDR, including Atm, Atm-Rad3-related(ATR), and DNA-dependent-protein kinase(DNA-PK), tumor suppressor p53 is one of the important substrates of Atm, and it can regulate cell cycle by inducing p21Cip1 expression, and induce cell apoptosis by Puma, Bax and so on.As such, p53 is called as the guardian of genome.Mdm2 is an important negative regulator of p53.As the E3 ubiquitin ligase, it regulate the stability of p53.Atm/Atr’s substrates also include Chk1 and Chk2, and they can activate G2/M checkpoint via Cdc25.ATM/ATR-p53 and ATM/ATR-CHK1/2-CDK are all classical damage response pathways. In addition, there are also alternative DNA damage response pathways, such as p38MAPK-Atf2 and BMP-Smad1 mediated damage respond pathways, which also play important roles in regulation of cell cycle and apoptosis.Here we report that p57Kip2, a CDK inhibitor implicated in the development of tumor-prone Beckwith-Wiedemann syndrome, is an effector molecule of the DNA damage response. Genotoxic stress induces p57Kip2 expression via the BMP-Smad1 and Atm-p38MAPK-Atf2 pathways in p53 proficient or deficient cells, and requires the Smad1-Atf2 complex that facilitates their recruitment to the p57Kip2 promoter. Elevated p57Kip2 induces G1/S phase cell cycle arrest but inhibits cell death in response to DNA damage and acts in parallel with p53 to suppress cell transformation and tumor formation. p57Kip2 is also upregulated in stage I and II clinical rectal tumors samples, likely due to genome instability of precancerous and/or early cancer cells. Targeting p57Kip2 in primary rectal cancer cells and tumor models resulted in increased sensitivity to doxorubicin, suggesting that p57Kip2 plays a role in chemoresistance, which is consistent with its pro-survival function. These findings place p57Kip2 in DNA damage response and uncover molecular mechanisms by which p57Kip2 suppresses tumorigenesis and causes chemoresistance.Many chemotherapeutic drugs can cause DNA damage. Many of the drugs also have side effects which limit its clinic usage.As common chemotherapy drugs, Dox and other members of chemotherapeutic drugs induce dose dependent cardiac toxicity. There are evidence that the formation of Doxorubicin cardiac toxicity is related to oxidative stress, iron metabolism imbalance, calcium overload, energy metabolic disorders, mitochondrial damage and cellular apoptosis. We suspect that DNA damage response might be involved. To test this theory, we began with the classical DNA damage response Atm-p53 pathway. We studied Dox-induced cardiac toxicity in Atm-/-and p53-/-mice. It was found that Atm-/- mice were more sensitive andp53-/-mice did not show a difference compared to control. However, Dox and anthracycline-based drugs can cause the alternative splicing of Mdm2, that making Mdm2 protein lost E3 ubiquitin ligase. As an E3 ubiquitin enzyme, Mdm2 may also target other proteins besides p53.In addition, we found that cardiac toxicity induced by Dox was related with the balance of Calcium.PLN, a Ca2+regulatorin cardiomyocyte, extend the lifespan in response.Further study is needed to testwhether PLN is under the influence of Atm or Mdm2. |
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