A growing number of important cell cycle regulators such as Cdks, checkpoint kinases (Chks), polo-like kinases (Plks), Aurora kinases, NIMA-related kinases (Neks), p53, BRCA1, and cyclin B1 have been shown to localize to the centrosome (Table ?(Table1).1). progress against this disease, the two most important goals for cancer researchers are to fully understand the molecular basis of cancer and to develop effective therapies for it. One of the hallmarks of carcinogenesis is dysregulation of the cell cycle [3]. Cell cycle is controlled at a number of checkpoints. When cells suffer extracellular or intracellular stress or both, the cell-cycle checkpoints, especially G1/S and G2/M checkpoints which are controlled by a number of complexes that are composed of cyclin-dependent kinases (Cdks), cyclins, and their negative regulators including the Cip/Kip family members and the INK4a/ARF family members [4-6], are activated. The G1/S checkpoint is the first surveillance system to stop DNA synthesis when cells suffer from extracellular stresses and it is an effective step to control cell proliferation and apoptosis. The mechanism of G1/S checkpoint is extensively studied [5-8]. The G2/M checkpoint prevents DNA-damaged cells from entering mitosis and allows for the repair of DNA that was damaged in late S or G2 phases prior to mitosis. The G2/M checkpoint is controlled by Cdc2/cyclinB, and their negative regulators including p21Cip1 and p27 [9]. Weakened G2/M checkpoint under therapeutic setting may trigger cell death via mitotic catastrophe for cells with unrepairable DNA lesions and mitosis machinery. This may represent a novel strategy to kill cancer cells, especially those with the p53 mutant phenotype which could result in inactivation or lost Jionoside B1 of the G1/S checkpoint in cancer [10,11]. Thus, the G2/M checkpoint is a potential target for cancer therapy. As the primary microtubule-organizing center (MTOC), the centrosome plays an important role in maintaining chromosome stability by establishing bipolar mitotic spindles. Accumulating evidence suggests that centrosome integrates cell-cycle arrest and repair signals in response to genotoxic stress [12]. A growing number of important cell cycle regulators such as Cdks, checkpoint kinases (Chks), polo-like kinases (Plks), Aurora kinases, NIMA-related kinases (Neks), p53, BRCA1, and cyclin B1 have been shown to localize to the centrosome (Table ?(Table1).1). All of those proteins have been implicated in participating in G2/M checkpoint control and in the regulation of centrosome separation [13-20]. Abnormal expression (either under or over) of these proteins has been observed in most cancers [21] and they have been found to directly influence the efficacy of antitumor agents [22]. Thus, manipulating these G2/M checkpoint proteins could enhance cancer’s sensitivity to radiotherapy and chemotherapy. In this review we focus on centrosome-associated regulators of G2/M checkpoint and potential targets for cancer chemotherapeutic therapy. Table 1 Centrosome-associated G2/M checkpoint proteins thead Centrosome proteinsSubstratesFunctionsEffects of expression manipulation /thead cyclin B/Cdk1 [33]Drp1/Dnml1, HuR, hnRNP-k, TPX2mitosis entry, bipolar spindle assemblyinhibition: induce cell cycle arrest and apoptosisAurora A[34,35,76]centrosomin, -TuRC, Eg5, Ran-TPX2, CENP-A, PP1, p53, Cdh1, NM23-H1, CPEB, Cdc25B, TPX2mitotic entry and exit, centrosome mutation and separation, spindle formationinhibition: monopolar spindle overexpression: centrosome amplification and loss of mitotic checkpointAurora B[34,35]INCEP, Survivin, BubR1, Mad2chromatid separation, spindle assembly checkpointinhibition: multinucleate cellsPlk1[21,34,36]Cdc25, cyclinB/Cdk1, p53, Nlp1, ATM/ATR, BRCA1, Chk1, Emi1, Wee1mitotic entry and exit, APC/C regulation, bipolar spindle formation, centrosome maturation,inhibition: smaller centrosomesNek2A[18,34,101]PP1, C-Nap1centrosome separation and maturation, mitotic entryoverexpression: split centrosomesSurvivin[90,91,102]Caspases 3, 7, 9, Aurora B, INCENPanti-apoptosisinhibition: loss of mitotic kinases and checkpoint, supernumerary centrosomep53[47,48]p21, 14-3-3, GADD45centrosome duplicationinhibition: centrosome amplicationBRCA1[51,52]-Tubulin, Chk1/2, p53, Cdc25, Wee1, Aurora Acentrosome duplicationinhibition: centrosome re-duplication and hyperactive MT nucleationAPC/C[99]Cyclin B/Cdk1, securin, Aurora A, Plk1, Cdk2sister.Since alteration of cell-cycle control is a hallmark of tumorigenesis, cell-cycle regulators represent potential targets for therapy. has an important role in G2/M checkpoint function. In this review, we discuss centrosome-associated regulators of the G2/M checkpoint, the dysregulation of this checkpoint in cancer, and potential candidate targets for cancer therapy. Introduction With the aging of the world’s population, the westernization of diet, and the increasing environmental pollution associated with the global economy, cancer has emerged as the top threat to human life worldwide [1,2]. To advance our progress against this Rabbit Polyclonal to MYB-A disease, the two most important goals for cancer researchers are to fully understand the molecular basis of cancer and to develop effective therapies for it. One of the hallmarks of carcinogenesis is dysregulation of the cell cycle [3]. Cell cycle is controlled at a number of checkpoints. When cells suffer extracellular or intracellular stress or both, the cell-cycle checkpoints, especially G1/S and G2/M checkpoints which are controlled by a number of complexes that are composed of cyclin-dependent kinases (Cdks), cyclins, and their negative regulators including the Cip/Kip family members and the INK4a/ARF family members [4-6], are activated. The G1/S checkpoint is the first surveillance system to stop DNA synthesis when cells suffer from extracellular stresses and it is an effective step to control cell proliferation and apoptosis. The mechanism of G1/S checkpoint is extensively studied [5-8]. The G2/M checkpoint prevents DNA-damaged cells from entering mitosis and allows for the repair of DNA that was damaged in late S or G2 phases prior to mitosis. The G2/M checkpoint is controlled by Cdc2/cyclinB, and their negative regulators including p21Cip1 and p27 [9]. Weakened G2/M checkpoint under therapeutic setting may trigger cell death via mitotic catastrophe for cells with unrepairable DNA lesions and mitosis machinery. This may represent a novel strategy to kill cancer cells, especially those with the p53 mutant phenotype which could result in inactivation or lost of the G1/S checkpoint in cancer [10,11]. Thus, the G2/M checkpoint is a potential target for cancer therapy. As the primary microtubule-organizing center (MTOC), the centrosome plays an important role in maintaining chromosome stability by establishing bipolar mitotic spindles. Accumulating evidence suggests that centrosome integrates cell-cycle arrest and repair signals in response to genotoxic stress [12]. A growing number of important cell cycle regulators such as Cdks, checkpoint kinases (Chks), polo-like kinases (Plks), Aurora kinases, NIMA-related kinases (Neks), p53, BRCA1, and cyclin B1 have been shown to localize to the centrosome (Table ?(Table1).1). All of those proteins have been implicated in participating in G2/M checkpoint control and in the Jionoside B1 regulation of centrosome separation [13-20]. Abnormal expression (either under or over) of these proteins has been observed in most cancers [21] and they have been found to directly influence the efficacy of antitumor agents [22]. Thus, manipulating these G2/M checkpoint proteins could enhance cancer’s level of sensitivity to radiotherapy and chemotherapy. With this review we focus on centrosome-associated regulators of G2/M checkpoint and potential focuses on for malignancy chemotherapeutic therapy. Table 1 Centrosome-associated G2/M checkpoint proteins thead Centrosome proteinsSubstratesFunctionsEffects of manifestation manipulation /thead cyclin B/Cdk1 [33]Drp1/Dnml1, HuR, hnRNP-k, TPX2mitosis access, bipolar spindle assemblyinhibition: induce cell cycle arrest and apoptosisAurora A[34,35,76]centrosomin, -TuRC, Eg5, Ran-TPX2, CENP-A, PP1, p53, Cdh1, NM23-H1, CPEB, Cdc25B, TPX2mitotic access and exit, centrosome mutation and separation, spindle formationinhibition: monopolar spindle overexpression: centrosome amplification and loss of mitotic checkpointAurora B[34,35]INCEP, Survivin, BubR1, Mad2chromatid separation, spindle assembly checkpointinhibition: multinucleate cellsPlk1[21,34,36]Cdc25, cyclinB/Cdk1, p53, Nlp1, ATM/ATR, BRCA1, Chk1, Emi1, Wee1mitotic access and exit, APC/C rules, bipolar spindle formation, centrosome maturation,inhibition: smaller centrosomesNek2A[18,34,101]PP1, C-Nap1centrosome separation and maturation, mitotic entryoverexpression: split centrosomesSurvivin[90,91,102]Caspases 3, 7, 9, Aurora B, INCENPanti-apoptosisinhibition: loss of mitotic kinases and checkpoint, supernumerary centrosomep53[47,48]p21, 14-3-3, GADD45centrosome Jionoside B1 duplicationinhibition: centrosome amplicationBRCA1[51,52]-Tubulin, Chk1/2, p53, Cdc25, Wee1, Aurora Acentrosome duplicationinhibition: centrosome re-duplication and hyperactive MT nucleationAPC/C[99]Cyclin B/Cdk1, securin, Aurora A, Plk1, Cdk2sister chromatid separation, mitotic exit, proteasomal degradationNAATM/ATR[55]p53, Chk1/2, BRCA1, Mdm2initiation of genotoxic stress responseNAChk1/2 [56-59]Cdc25, BRCA1, E2F, p73centrosome separation, mitotic entryinhibition: centrosome amplification and mitotic arrest Open in a separate window Cell cycle and centrosomal cycle The cell cycle entails a repeating sequence of events that include the duplication of cellular contents and subsequent cell division. Traditionally, the cell cycle in the eukaryotic cell is definitely divided into four phases: Gap phase 1 (G1); DNA synthesis phase.