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Wee1 and Chk1 - crosstalk between key players in replicative stress.

Saini P, Li Y, Dobbelstein M - Genes Cancer (2015)

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Oncology, Ernst Caspari Haus, Göttingen Center of Molecular Biosciences, Faculty of Medicine, University of Göttingen, Göttingen, Germany.

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Replicative stress is a tumor cell-associated feature that includes the accumulation of stalled or collapsed replication forks... With the DNA polymerases lagging behind the helicases, these structures contain extended regions of single stranded DNA, leading to the activation of a damage signaling pathway that includes the kinases Ataxia Telangiectasia Mutated-Related (ATR) and Chk1... In particular, interfering with ATR-Chk1 signaling promotes the death of proliferating cancer cells, and inhibitors of both kinases are currently evaluated in clinical trials... We firstly induced replicative stress in our experimental systems using the nucleoside analogue gemcitabine... Under these conditions, we eliminated the activity of Wee1 and its downstream effectors by pharmacological inhibition or by siRNA... As a result, we found that Wee1 inhibition indirectly reduces Chk1 activity as well, by activating cyclin dependent kinases and subsequently suppressing the functions of ATR and the Chk1-coactivator Claspin... Despite the simultaneous impairment of Chk1 activity by Wee1 inhibitors, combining inhibitors of Wee1 and Chk1 may nonetheless prove useful to eliminate cancer cells... Also, inhibitors of DNA replication, such as nucleoside or base analogues, can be employed to enhance different regimens of cancer treatment... For instance, the Dobbelstein lab has recently observed that the base analogue 5-fluorouracil interferes with homologous recombination repair; it thus augments the damage induced by double strand DNA breaks, as they occur through ionizing irradiation... Exploiting replicative stress for cancer treatment is a strategy that can strongly benefit from the combination of conventional DNA-damaging cancer drugs with targeted signaling inhibitors... Knowing about the cross-talks between these signaling components has the potential of further improving this approach and to identify tumor-cell associated markers for optimizing therapeutic combinations.

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Related in: MedlinePlus

Molecular communication between Wee1 and Chk1 (adapted and expanded from [7])Wee1 inhibition can be achieved by direct small molecule inhibitors, or otherwise by HSP90 inhibition [9]. Chk1 and ATR are subject to similar inhibition strategies. Kinase activities mediate signaling cross-talk as depicted. Blue arrows indicate pathways investigated in the new study [7], black arrows refer to available literature. Collectively, the model suggests mutual dependence of Wee1 and Chk1 on each other's activities.
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Figure 1: Molecular communication between Wee1 and Chk1 (adapted and expanded from [7])Wee1 inhibition can be achieved by direct small molecule inhibitors, or otherwise by HSP90 inhibition [9]. Chk1 and ATR are subject to similar inhibition strategies. Kinase activities mediate signaling cross-talk as depicted. Blue arrows indicate pathways investigated in the new study [7], black arrows refer to available literature. Collectively, the model suggests mutual dependence of Wee1 and Chk1 on each other's activities.


Wee1 and Chk1 - crosstalk between key players in replicative stress.

Saini P, Li Y, Dobbelstein M - Genes Cancer (2015)

Molecular communication between Wee1 and Chk1 (adapted and expanded from [7])Wee1 inhibition can be achieved by direct small molecule inhibitors, or otherwise by HSP90 inhibition [9]. Chk1 and ATR are subject to similar inhibition strategies. Kinase activities mediate signaling cross-talk as depicted. Blue arrows indicate pathways investigated in the new study [7], black arrows refer to available literature. Collectively, the model suggests mutual dependence of Wee1 and Chk1 on each other's activities.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482240&req=5

Figure 1: Molecular communication between Wee1 and Chk1 (adapted and expanded from [7])Wee1 inhibition can be achieved by direct small molecule inhibitors, or otherwise by HSP90 inhibition [9]. Chk1 and ATR are subject to similar inhibition strategies. Kinase activities mediate signaling cross-talk as depicted. Blue arrows indicate pathways investigated in the new study [7], black arrows refer to available literature. Collectively, the model suggests mutual dependence of Wee1 and Chk1 on each other's activities.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Oncology, Ernst Caspari Haus, Göttingen Center of Molecular Biosciences, Faculty of Medicine, University of Göttingen, Göttingen, Germany.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Replicative stress is a tumor cell-associated feature that includes the accumulation of stalled or collapsed replication forks... With the DNA polymerases lagging behind the helicases, these structures contain extended regions of single stranded DNA, leading to the activation of a damage signaling pathway that includes the kinases Ataxia Telangiectasia Mutated-Related (ATR) and Chk1... In particular, interfering with ATR-Chk1 signaling promotes the death of proliferating cancer cells, and inhibitors of both kinases are currently evaluated in clinical trials... We firstly induced replicative stress in our experimental systems using the nucleoside analogue gemcitabine... Under these conditions, we eliminated the activity of Wee1 and its downstream effectors by pharmacological inhibition or by siRNA... As a result, we found that Wee1 inhibition indirectly reduces Chk1 activity as well, by activating cyclin dependent kinases and subsequently suppressing the functions of ATR and the Chk1-coactivator Claspin... Despite the simultaneous impairment of Chk1 activity by Wee1 inhibitors, combining inhibitors of Wee1 and Chk1 may nonetheless prove useful to eliminate cancer cells... Also, inhibitors of DNA replication, such as nucleoside or base analogues, can be employed to enhance different regimens of cancer treatment... For instance, the Dobbelstein lab has recently observed that the base analogue 5-fluorouracil interferes with homologous recombination repair; it thus augments the damage induced by double strand DNA breaks, as they occur through ionizing irradiation... Exploiting replicative stress for cancer treatment is a strategy that can strongly benefit from the combination of conventional DNA-damaging cancer drugs with targeted signaling inhibitors... Knowing about the cross-talks between these signaling components has the potential of further improving this approach and to identify tumor-cell associated markers for optimizing therapeutic combinations.

No MeSH data available.


Related in: MedlinePlus