Given these apparent dif ferences, only our overall conclusions are in accord with selleck chem those of Zhu et al. We also propose that inhibiting geminin expression and or activity should selectively kill cancer cells overexpressing geminin. Decreased repair of chromosomal DSBs can lead to genome instability, including mutation, translocation and aneuploidy, all of which are hallmarks of many can cers. Interestingly, specific Chk1 Inhibitors,Modulators,Libraries and H2AX phosphatase upregulation in geminin overexpression led to their inactivation in Gem9 cells. Taken together, our present findings suggest that geminin overexpression induces the formation of aneu ploid, aggressive and drug resistant breast cancer cells. Geminin silencing pre vents decatenation Inhibitors,Modulators,Libraries because it blocks TopoIIas access to chromosomes and its function therein.
Thus, in combination, our data pro vide an intriguing molecular explanation for the high percentage of patients Inhibitors,Modulators,Libraries in whom TopoIIa directed treat ment fails. We propose that etoposide, doxorubicin or any other drugs that target TopoIIa function will be more beneficial when combined with anti geminin che motherapeutic agents. Conclusions In summary, our data provide strong evidence that geminin plays a critical role in mitotic chromosome decatenation and or segregation. The role of geminin in these processes reflects its ability to influence TopoIIa chromosome localization and activity during the G2 M early G1 phase. The specific timing of gemi nins association with chromosomes and its regulation of TopoIIa chromosome localization and function in the G2 M early G1 phase fit the role of geminin in the induction of proper cytokinesis that we proposed ear lier.
Our results have established a significant role for geminin via its functional and physical interactions with Cdc7 and or CKI�� Inhibitors,Modulators,Libraries and TopoIIa, respectively, in the complex process of mitotic chromosome segrega tion and execution of proper cytokinesis. As such, geminin represents an extremely attractive target for chemotherapy interventions for aggressive breast can cer, either alone or in combination with TopoIIa drugs. Our findings have wide significance in providing new insight into how geminin could be involved in gene amplification and translocation in cancer. We suggest that lack of religation during the decatenation cycle by prematurely releasing TopoIIa from the decatenation sites can lead to illegitimate repair and genome rearran gement.
Our data also lead us to question previous assumptions concerning the existence of a checkpoint for preventing cells with an incompletely replicated and or segregated genome from entering mitosis and becom ing aneuploid. Breast cancer continues to be the second Inhibitors,Modulators,Libraries leading cause of cancer related deaths among women worldwide. Approximately 70% of breast cancers are estrogen recep tor a positive and progesterone receptor http://www.selleckchem.com/products/mek162.html positive.