Disease relevance of Chek2

• To examine the role of Chk2 in p53-dependent apoptotic response, we used adenovirus E1A-expressing MEFs [1].
• The checkpoint kinase, Chk2, has been implicated in both of these responses and is believed to function in an ataxia telangiectasia (Atm)-dependent manner [1].
• Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner [2].
• Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome [2].

High impact information on Chek2

• Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 53BP1 in response to DNA damage [3].
• In this cell line, both USP28 and Chk2 are required for DNA-damage-induced apoptosis, and they accomplish this in part through regulation of the p53 induction of proapoptotic genes like PUMA [3].
• IR-induced stabilization of p53 in Chk2(-/- )cells was 50-70% of that in wild-type cells [4].
• The IR-induced G(1)/S cell cycle checkpoint, but not the G(2)/M or S phase checkpoints, was impaired in embryonic fibroblasts derived from Chk2(-/-) mice [4].
• Although Chk2(-/-) mice appeared normal, they were resistant to ionizing radiation (IR) as a result of the preservation of splenic lymphocytes [4].

Chemical compound and disease context of Chek2

• IR-induced apoptosis was restored in Chk2(-/-) thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3(+) related (ATR) were mutated to alanine [2].

Biological context of Chek2

• The mammalian Chk2 kinase is thought to mediate ATM-dependent signaling in response to DNA damage [4].
• We show that Chk2-/- cells, like p53-/- cells, did not undergo DNA damage-induced apoptosis, whereas Atm-/- cells behaved like normal cells in invoking an apoptotic response [1].
• Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation [2].
• Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes [5].
• Among these targets, inhibition of chk2 may induce cell death for tumors whose growth depends on enhanced chk2 activity [6].

Anatomical context of Chek2

• In ES cells, Chk2 kinase is not intranuclear as in somatic cells but is sequestered at centrosomes and is unavailable to phosphorylate Cdc25A phosphatase and cause its degradation [7].
• Tissues from Chk2(-/-) mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G(1)/S arrest [2].

Associations of Chek2 with chemical compounds

• Furthermore, suppression of AKT by plumbagin enhanced the activation of Chk2, resulting in increased inactive phosphorylation of Cdc25C and Cdc2 [8].

Regulatory relationships of Chek2

• Likewise, Hus1 was dispensable for genotoxin-induced Chk2 phosphorylation [9].
• However, in our present paradigms, we show that ATM functions separately from Chk2 to regulate p53 stability and neuronal death [10].

Other interactions of Chek2

• These data indicate that 53BP1 acts downstream of ATM and upstream of Chk2 in the DNA damage response pathway and is involved in tumor suppression [11].
• We have recently shown that Chk2 and the DNA-dependent protein kinase (DNA-PK) are both involved in DNA damage-induced apoptosis but not G(1) arrest in mouse embryo fibroblasts [12].
• Although ectopic expression of Chk2 does not rescue the p53/p21 pathway, its expression is sufficient to allow it to phosphorylate Cdc25A, activate downstream targets, restore a G(1) arrest, and protect the cell from apoptosis [7].

References