Biology Reference
In-Depth Information
catastrophe, indicating that MK2 is the crucial downstream effector of
p38MAPK in the checkpoint response. To further investigate the role of
MK2 in cell survival after genotoxic stress in a more cancer-specific context,
studies were performed in cells following cisplatin-induced intrastrand cross-
links as well as after DNA breaks induced by topoisomerase inhibitors such as
doxorubicin,
26
two agents commonly used in anticancer therapy. Depletion of
MK2 in p53-proficient and p53-deficient MEFs revealed that the function
of this pathway is especially important for cell cycle arrest and prevention of
apoptosis in the context of defective p53 function. MK2 activity was dispens-
able for survival in p53 wild-type cells after both cisplatin and doxorubicin
treatment. In p53-deficient cells, however, loss of MK2 resulted in a markedly
increased sensitivity to DNA-damaging chemotherapy, particularly at low doses
of these genotoxic agents.
Studies on allograft tumors in mice derived from transformed H-Ras
V12
and p53-deficient MEFs confirmed these results. When the tumors were
examined for chemosensitivity, knockdown of MK2 was found to result in a
dramatically increased tumor regression following systemic treatment with
cisplatin or doxorubicin
in vivo
. This synthetic lethality between p53 and
MK2 could be explained by the fact that p53-deficient cells lacking MK2
activity could initiate, but were unable to maintain, functional G1/S and
G2/M cell cycle checkpoints at late times after DNA damage as a consequence
of the reduced levels of Cdc25A, B, and C phosphorylation.
26
Furthermore,
studies on the subcellular localization of MK2, compared with Chk1, explained
the requirement for both effector checkpoint kinases.
27
Chk1 activity arises
early after damage and is largely localized to the nuclear compartment. In
contrast, MK2 activity is prolonged at times long after Chk1 activity has ceased,
and the active form of MK2 is primarily found in the cytoplasm. These results
suggested that in p53-proficient cells, damage-induced activation of p53 main-
tains the cell cycle checkpoint when Chk1 activity fades, and that in the
absence of p53, MK2 subsumes this function. These results suggest that
MK2 might be an ideal therapeutic target for use in chemosensitizing p53-
defective tumors to specific types of chemotherapy. A variety of small-molecule
inhibitors of MK2 are in various stages of development, although their use in
cancer treatment trials is still unclear.
1. I
NHIBITION OF THE
C
HK
1T
ARGET
W
EE
1
In addition to the major DNA damage response kinases ATM/Chk2, MK2,
and ATR/Chk1, other molecules involved in maintaining the G2/M cell cycle
checkpoint arrest have recently been identified as potential druggable targets
for a synthetic lethal approach to treat p53-deficient tumors with higher
efficiency. One of them is Wee1, a protein kinase activated by Chk1 in DNA
damage response and replication stress signaling. Wee1 is directly responsible
