Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner.

Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Ontario M5G 2C1, Canada.
Molecular and Cellular Biology (Impact Factor: 5.04). 10/2002; 22(18):6521-32. DOI: 10.1128/MCB.22.18.6521-6532.2002
Source: PubMed

ABSTRACT In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated gene-targeted Chk2-deficient mice. Unlike ATM(-/-) and p53(-/-) mice, Chk2(-/-) mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. 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. Quantitative comparison of the G(1)/S checkpoint, apoptosis, and expression of p53 proteins in Chk2(-/-) versus ATM(-/-) thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. 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. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome maintenance in germ cells is critical for fertility and the stable propagation of species. While mechanisms of meiotic DNA repair and chromosome behavior are well-characterized, the same is not true for primordial germ cells (PGCs), which arise and propagate during very early stages of mammalian development. Fanconi anemia (FA), a genomic instability syndrome that includes hypogonadism and testicular failure phenotypes, is caused by mutations in genes encoding a complex of proteins involved in repair of DNA lesions associated with DNA replication. The signaling mechanisms underlying hypogonadism and testicular failure in FA patients or mouse models are unknown. We conducted genetic studies to show that hypogonadism of Fancm mutant mice is a result of reduced proliferation, but not apoptosis, of PGCs, resulting in reduced germ cells in neonates of both sexes. Progressive loss of germ cells in adult males also occurs, overlaid with an elevated level of meiotic DNA damage. Genetic studies indicated that ATM-p53-p21 signaling is partially responsible for the germ cell deficiency.
    PLoS Genetics 07/2014; 10(7):e1004471. · 8.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mammalian checkpoint kinases 1 and 2 (Chk1 and Chk2) are essential kinases that are involved in cell cycle checkpoint control, and the abrogation of either has been proposed as one way to sensitize cancer cells to DNA-damaging agents. However, it remains unclear which kinase is the most therapeutically relevant target, and whether multiple kinases might need to be targeted to achieve the best efficacy because of their overlapping substrate spectra and redundant functions. To clarify this issue, we established asynchronous cell cycle arrest models to investigate the therapeutic outcomes of silencing Chk1 and Chk2 in the presence of irradiation or cisplatin. Our results showed that Chk1- and Chk2-targeting small interference RNAs (siRNAs) demonstrated synergistic effects when both siRNAs were used simultaneously. Interestingly, Chk1 and Chk2 co-expression occurred in ∼90% of neoplastic tissues examined and showed no difference in neoplastic versus non-neoplastic tissues. Therefore, the selective targeting of Chk1 and Chk2 by oncolytic adenovirus mutants was chosen to treat resistant tumor xenograft mice, and the maximum antitumoral efficacy was achieved with the combined co-abrogation of Chk1 and Chk2 in the presence of low-dose cisplatin. This work deepens our understanding of novel strategies that target checkpoint pathways and contributes to the development of novel, potent and safe checkpoint abrogators.Cancer Gene Therapy (2014) 21, 209-217; doi:10.1038/cgt.2014.20; published online 23 May 2014.
    Cancer gene therapy 05/2014; · 3.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Checkpoint kinase 2 (CHK2) is a downstream effector of the DNA damage response (DDR). Dysfunctional telomeres, either owing to critical shortening or disruption of the shelterin complex, activate a DDR, which eventually results in cell cycle arrest, senescence and/or apoptosis. Successive generations of telomerase-deficient (Terc) mice show accelerated aging and shorter lifespan due to tissue atrophy and impaired organ regeneration associated to progressive telomere shortening. In contrast, mice deficient for the shelterin component TRF1 in stratified epithelia show a rapid and massive induction of DDR, leading to perinatal lethality and severe skin defects. In both mouse models, p53 deficiency can rescue survival. Here, we set to address the role of CHK2 in signaling telomere dysfunction in both mouse models. To this end, we generated mice doubly deficient for Chk2 and either Terc (Chk2(-/-) Terc(-/-) ) or Trf1 (Trf1(Δ/Δ) K5Cre Chk2(-/-) ). We show that Chk2 deletion improves Terc-associated phenotypes, including lifespan and age-associated pathologies. Similarly, Chk2 deficiency partially rescues perinatal mortality and attenuates degenerative pathologies of Trf1(Δ/Δ) K5Cre mice. In both cases, we show that the effects are mediated by a significant attenuation of p53/p21 signaling pathway. Our results represent the first demonstration of a role for CHK2 in the in vivo signaling of dysfunctional telomeres.
    Aging cell 06/2014; · 7.55 Impact Factor

Full-text (2 Sources)

Available from
May 28, 2014