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6 Seema TRIVEDI TACC1 may also be involved in gene regulation by affecting mRNA translation by interaction with TDRD7 (tudor domain containing 7) (Figure 1). TDRD7 protein is a part of cytoplasmic RNA granules involved in mRNA regulation. It is not known whether the involvement of TACCs in RNA processing or interaction with transcription factors has any role in MT dynamics during cell division. As per Figure 1, TACC1 and 3 also interact with AURKB and AURKA. These two proteins also interact with Cyclin B1 (which controls entry in mitosis) (Conte et al., 2002). Studies have shown that TACC3 is involved in localization of the mitotic kinase Aurora B and the checkpoint protein BubR1 at kinetochores thus affecting MT attachment (Schneider et al., 2007). TACC2 protein also directly interacts with SMYD2 (SET- and MYND-containing protein 2) (Figure 1). SMYD2 activates TACC2 gene by methylation of H3K4 in the promoter region of TACC2 gene besides the involvement of SMYD2 in some protein-protein interactions. These protein interactions may have roles in centrosomal MT formation (Abu-Farha et al., 2008) but apparently not by directly interacting with TACC2 protein. Phosphorylated TACC3 also directly interacts with clathrin heavy chain (CLTC) that promotes accumulation of other complex members at the mitotic spindle (reviewed in Hood and Royle, 2011). Another direct interaction of TACC3 protein with septin-7 (SEPT7, CDC10 protein homolog) is shown in Figure 1. SEPT7 associates with the mitotic spindle and the kinetochore. It has also been shown that SEPT7 is needed for stable localization of CENP-E (centromere-associated protein E) at kinetochore besides affecting spindle checkpoint (Zhu et al., 2008). Association of SEPT7 and MAPs, particularly MAP4, in MT dynamics both during interphase and mitosis has been established (Silverman-Gavrila et al., 2008), and it is possible that similar interaction of SEPT7 with TACC proteins may affect MT stability. Expression of TACC3 is high in hematopoietic tissue unlike TACC1 and TACC2. Apparently higher levels of TACC3 proteins are not for proliferation of tissue but for direct or indirect regulation of p53 levels to prevent apoptosis although not true for other tissue (Piekorz et al., 2002). Other study confirmed direct interaction of TACC3 with p53 (that is also concentrated at centrosomes) possibly to keep it inactive during mitosis (reviewed in Raff, 2002) (not seen in Figure 1). TACC3 is necessary for proper localization of phosphorylated TSC2 (Tuberous sclerosis proteins, tuberin) to the mitotic apparatus and cytokinetic structures. This interaction may be through the TSC2- HBD domain (TSC2 hamartin-binding domain) and result in promotion of cytoskeletal remodeling (Gómez-Baldó et al., 2010). Though little is known about the factors that control or regulate length of spindle fibers, TACC3 may be one of the proteins that control length of MTs and time for chromosome alignment at metaphase plate (reviewed in Raff, 2002). AAK may also regulate MT length, as seen in Drosophila embryos, where AAK function disturbance leads to abnormal shortening of centrosomal MTs. This disturbance also leads to inefficient concentration of D-TACC at centrosomes (reviewed in Raff, 2002). TACCs dysregulation and cancer Human TACC 1, 2 and 3 are present in genomic regions that are rearranged in certain cancer cells (reviewed in Raff, 2002; Stewart et al., 2004; Still et al., 1999). Aberrations of TACC genes (TACC3 in particular) contribute to tumorigenesis/cancer (reviewed in Raff, 2002; Lauffart et al., 2005). Since TACC proteins are also involved in centrosomal dynamics, cell cycle checkpoints (Schneider et al., 2007) and can form multiple complexes, any dysregulation in these proteins may be important during tumorigenesis (Lauffart et al., 2002). It has been noted that increase or decrease in levels of the TACCs can lead to impairment of spindle functions (reviewed in Raff, 2002). Disruption of spindle function can then lead to misalignment of chromosomes and or abnormalities in chromosome separation. Altered levels of TACC proteins can lead to abnormal mitosis although next p53 dependent checkpoint should eliminate such cells. However, if there is simultaneous alteration in TACC levels and p53 is either absent or depleted, then such cells would not
TACC proteins in spindles 7 Figure 1. Predicted functional partnes (minimum interaction) of the three TACC proteins (as per STRING Jensen et al., 1999) undergo elimination, resulting in genetic instability that could contribute to the development of cancer (reviewed in Raff, 2002). Some studies show that TACC3 may enhance stability of tumors. This can be achieved by TACC3 and ch-TOG in clustering of multipolar spindles in tumor cells into two poles that may lead to somewhat ‘normal’ division (reviewed in Hood and Royle, 2011). However, TACC2 may be a potential tumour suppressor (reviewed in Raff, 2002) contrary to studies that suggest no role of TACC2 in tumor suppression (Schuendeln et al., 2004). Unanswered questions Though much is known regarding TACC function in spindle and microtubule dynamics, there are few aspects that still remain unknown. These are summarized below: Roles of TACCs in regulation/control of spindle fiber lengths are not fully understood. Though the levels of TACC and particularly roles of TACC3 and AAK are indicated in control of MT length (reviewed in Raff, 2002), the precise mechanism by which this is achieved is not known. Though TACC proteins are present in cytoplasm during interphase, their fate at the end of mitosis is not known with respect to their redistribution to cytoplasm of the daughter cells. If there is exclusion/reduction in amount of TACC proteins from nucleoplasm, the mechanism remains elusive. Further, it is not known whether destruction/recycling/decrease in
Page 1 and 2: •Circadian rhythm genes in cancer
Page 3 and 4: Haliç University Faculty of Arts a
Page 5: Front cover image: “Cell division
Page 8 and 9: 2 Seema TRIVEDI the nucleation site
Page 10 and 11: 4 Seema TRIVEDI Table 2. Modificati
Page 14 and 15: 8 Seema TRIVEDI expression of all T
Page 16 and 17: 10 Seema TRIVEDI putative tumor sup
Page 18 and 19: 12 Yusuf ÖZŞENSOY ve Ercan KURAR
Page 26 and 27: Journal of Cell and Molecular Biolo
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Page 30 and 31: Figure 1. Amplification plots for M
Page 32 and 33: Determination of changes in gene ex
Page 34 and 35: eported. Thus, an increase in cytoc
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Page 40 and 41: Discussion The management of infert
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Page 60 and 61: 56 Mohan KANNAN et al. Table 1. Eff
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58 Mohan KANNAN et al. of flavonoid
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Journal of Cell and Molecular Biolo
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Sambrook J, Fritsch EF, Maniatis T.
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72 Mohamed R. ENAN Introduction Mat
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74 Mohamed R. ENAN Figure 2. Ethidi
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82 Sérgio Salla CHAGAS et al. Laur
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84 Abstract: A brief, informative a
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