Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br Chk and Chk mediated signaling act as a barrier

    2019-09-09


    Chk 1 and Chk 2 mediated signaling act as a barrier to tumorigenesis It was hypothesized recently that early events during tumorigenesis, such as the overexpression of oncogenes, lead to a DNA-damage response which, in turn halts tumor progression [44], [45], [46]. The DNA-damage response is proposed to act as a barrier to tumor progression by inducing both D-(-)-Salicin arrest and apoptosis [47]. This, in turn, leads to a selective pressure to inactivate the DNA-damage response pathways and in particular p53, something that also been demonstrated for hypoxia during tumor evolution [48]. These concepts further strengthen the link between the importance of genomic instability and tumor progression. The proposed mechanism for the induction of a DNA-damage response in precancerous lesions is through the overexpression of oncogenes. For example, in response to elevated activity of cyclin E, cells undergo uncontrolled DNA replication which, can result in not only premature progression through the cell cycle but also the formation of aberrant DNA replication intermediates [49]. These aberrant structures have been proposed to trigger the DNA-damage response pathway, beginning with ATM. These conclusions were backed by elegant data showing the phosphorylation of proteins commonly used as markers of DNA-damage in early superficial lesions, for example, Chk 2, histone H2AX and ATM [45], [46]. We and others would suggest that along with the amplification of oncogenes, the DNA-damage response pathway could be initiated by other factors during early tumor progression, for example, oxidative changes to DNA bases, the production of reactive oxygen species and hypoxia [44], [50], [51]. When oxygen levels are severely limited (0.02% O2) S-phase cells undergo a complete and rapid cessation of DNA synthesis leading to the accumulation of aberrant replication intermediates such as regions of single stranded DNA [31]. These are detected by ATM and more significantly the ATR kinase, via a mechanism that is most likely also dependent on both RPA and ATRIP [18], [52], [53]. In support of this, both Bartkova et al., and Gorgoulis et al., noted significant allelic imbalances at the sites of fragile sites in precancerous cells. This is interesting as ATR is required for the maintenance and stability of fragile sites during replication, therefore, indicating that ATR-mediated signaling of the DNA-damage response may also be significant during early tumorigenesis [33], [54]. This is further supported by the finding that both Chk 1 and Rad 17, which are ATR substrates, were both phosphorylated after induction of oncogene over-expression [46], [55], [56]. In summary, the DNA-damage response pathway can be initiated by hypoxia-induced replication arrest. In particular, ATR phosphorylates Chk 1 and ATM signals to Chk 2. Subsequent reoxygenation amplifies this response by inducing bona fide DNA damage [12]. The activation of these pathways may well have significant roles to play in the delay of tumorigenesis.
    Conclusions and future directions The critical roles of both Chk 1 and Chk 2 are highlighted by the absolute requirement for Chk 1 and the common occurrence of mutations in Chk 2 in human cancers. Given their roles in arresting the cell cycle, particularly in the G2 phase, they are sure to remain targets for new therapeutic strategies. As the reported roles for both Chk 1 and Chk 2 become increasingly more complicated, their targeted inhibition could well loose or gain momentum. The role for both Chk 1 and Chk 2 during the physiological stress of hypoxia/reoxygenation are sure to impact on the therapeutic use of such inhibitors. Of course, several unanswered questions remain, which need to be addressed by further study. For example exactly how early during early tumor progression does hypoxia occur, and does it precede or follow oncogene amplification? Perhaps more intriguingly why are some components of DNA-repair, such as Rad 51 and Brca 1, down-regulated by hypoxia, and what are the consequences of this after reoxygenation-induced DNA-damage?