TPX2

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Targeting protein for Xklp2 is a protein that in humans is encoded by the TPX2 gene. [1][2][3] It is one of the many spindle assembly factors that play a key role in inducing microtubule assembly and growth during M phase.

Key domains of TPX2

TPX2 has been reported to have two NLS-containing domains that mediate its localization to microtubules; one in the amino-terminal domain, and the other in the carboxy-terminal domain.[4][5] In addition to an NLS, the carboxy-terminal domain of TPX2 consists of tandem repeats that cover over two-thirds of the protein and are computationally predicted to consist of predominantly alpha-helical content.[6][7] This region can be further divided into five clusters of conserved residues separated by unstructured regions: α3-7.[7] α3-6 all contain a central α-helical region that is followed by a characteristic "FKARP" motif.[7] α7 is longer and exhibits a long α-helical stretch that is computationally predicted to form a coiled coil.[7] Lastly, the final 35 amino acids of the carboxy-terminus of TPX2 are responsible for interacting with tetrameric kinesin Eg5.[8][9]

TPX2 contains one KEN box (K-E-N) motif at amino acid 87 and three D-box (R-X-X-L) motifs at amino acids 119, 341, and 708.[10] Both motif types have been suspected to be important in regulation and degradation of TPX2 by the APC/C (see "Regulation of TPX2 in the Cell Cycle"), as typically mutations in these motifs render substrates resistant to ubiquitination by the APC/C.[11][12] However, in vitro ubiquitination assays have shown that only the first 83 amino acids of the N-terminal region of TPX2 along with the KEN box are pertinent for recognition by Cdh1, an activator of the APC/C.[10]

Role in microtubule assembly

TPX2 has been shown in several biochemical assays to behave as a microtubule-associated protein (MAP) and co-localize with spindle microtubules during M-phase.[1][13][14][5][15] It plays a role in microtubule nucleation and is regulated by importin proteins.

TPX2 serves as a complement, depleting importin α affinity in order to allow RanGTP-induced microtubule nucleation. This has been demonstrated both in vitro in Xenopus laevis egg extracts, and with the human homologue in vivo in HeLa cells.[16] [14] TPX2 is also important in activating and recruiting Aurora A kinase, a kinase responsible for phosphorylating TPX2 and essential for cell proliferation.[5] In the presence of nuclear import factor importin α, TPX2 is bound and prevented from binding Aurora A kinase, though it is still able to bind microtubules via its amino-terminal domain.[5] This leads to inhibition of M phase microtubule nucleation. In contrast, TPX2 is freed from inhibition by displacement of importin α via RanGTP, though RanGTP is not required for free TPX2 activity, as TPX2 has been shown to induce microtubule assembly in the absence of exogenous and depletion of endogenous RanGTP.[16] This suggests that TPX2 is downstream of RanGTP activity, but whether TPX2 is directly regulated by RanGTP still remains to be determined.

The mechanism by which TPX2 promotes microtubule nucleation has yet to be determined. One proposed mechanism has been based on TPX2's role in directly suppressing tubulin subunit off-rates at the microtubule tip during microtubule assembly and disassembly, verified by fluorescence microscopy.[17] This is made possible partially by TPX2's role in sequestering free tubulin subunits and nucleating small multi-subunit tubulin complexes, which inadvertently also slows the rate of growth by decreasing the effective free tubulin concentration.[17] TPX2's stabilization of the microtubule in its polymer form therefore contributes to microtubule nucleation. Computational simulations speculate that TPX2 suppresses tubulin subunit kinetics at the microtubule tip by randomly increasing the bond stability between adjacent tubulin subunits.[17]

In addition, TPX2 has been shown to be important in chromatin-dependent spindle assembly. Even with duplicated centrosomes, TPX2 has been demonstrated to be required for formation of a stable bipolar spindle with overlapping antiparallel microtubule arrays.[14] More specifically, TPX2 contributes to microtubule branching during spindle assembly by cooperating with augmin in order to amplify microtubule mass and preserve its polarity.[18] Branching nucleation by TPX2 is observed without RanGTP, though more fan-shaped microtubule structures are formed when both RanGTP and TPX2 are present.[18] The rate of branched formation is also enhanced in the presence of both components compared to Ran alone.[18]

The TPX2 region necessary for branching microtubule nucleation resides in its carboxy-terminal half (amino acids 319-716),[19] with TPX2 domains α5-7 as the minimal necessary requirement and domains α3-4 serving as contributors to nucleation efficiency by enabling earlier induction at faster rates. The amino-terminal half of TPX2 also increases the efficiency of the reaction.[7] TPX2 α5-7 is different from the remainder of the protein in that it contains conserved regions in its amino acid sequence that share sequence similarity with two known γ-TuRC nucleation activator motifs: SPM and γ-TuRC.[7] The SPM-like motif is found within the α5 domain, while the γTuNA-like motif is found to start in the α5 domain and stretch into the SPM-like motif. Without these two motifs, no microtubule nucleation was observed in vitro, though microtubule binding ability was maintained.[7] However, these two motifs are not the only essential ones in microtubule branching nucleation; the FKARP motifs of α5 and α6 are also essential for stimulating this process.[7] Furthermore, the α-helical region stretch of domain α7 and the C-terminal residues that interact with Eg5 are critical for microtubule branching nucleation as well.[7] While α5-7 domains are important in this process, none of them have intrinsic microtubule nucleation activity.[7]

In terms of binding to and bundling microtubules, at least any of the three domains α3-7 of TPX2 are necessary for significant binding and bundling in vitro.[7] Furthermore, it is likely that the domains cooperatively mediate microtubule binding and bundling, as successive addition or subtraction of a domain does not result in a linear change in microtubule binding and bundling capacity.[7]

Activation and reciprocation through Aurora A kinase

TPX2 recruits and activates Aurora A kinase by utilizing its short 43 amino acid long amino-terminal sequence to bind the catalytic domain of Aurora A, locking the kinase into its active conformation.[20][21] More specifically, this interaction positions the activation segment of the kinase into a more favorable conformation for substrate binding and swings the crucial phosphothreonine residue, a target usually exposed and accessible for deactivation of Aurora A kinase by PP1, into a buried position, thereby locking Aurora A into an active conformation.[20] Notably, this recognition between TPX2 and Aurora A is analogous to that between the cAMP-dependent protein kinase (cAPK) catalytic core and its flanking region, suggesting a recurring theme in kinase regulation.[20] Activated Aurora A in turn phosphorylates TPX2, but it is still unclear how Aurora A’s phosphorylation of TPX2 affects its activities.

Role in cleavage arrest and interaction with Eg5

When four-fold TPX2 over the endogenous level was injected into a blastomere with a two-cell embryo, cleavage arrest was induced.[8] This arrest has been attributed to the amino acids 471-715 of the carboxy-terminus of the TPX2 protein, with the last 35 amino acids being absolutely necessary for inducing cleavage arrest.[8] During cytokinesis failure, cycles of DNA synthesis and mitosis continue. Notably, spindle poles fail to segregate, leading to a failure to establish a bipolar spindle, a spindle midzone, and a central spindle complex.[8] Because cleavage furrow ingression is primarily triggered by signals from the spindle midzone,[22][23] these biological phenotypes could account for the failure of this event due to the inability to activate the spindle checkpoint.[8] Instead of a bipolar spindle, both spindle poles are in apposition, with an impairment of pushing forces generated by interpolar microtubules.[8]

The mechanistic cause behind cleavage arrest is attributed to TPX2’s ability to directly bind motor protein Eg5, which requires the last 35 amino acids of the TPX2 carboxy-terminus for its interaction.[8] When Eg5 was co-injected with TPX2 in vivo, cleavage furrow arrest was blocked and ingression was observed. This suggests that the carboxy-terminus of TPX2 regulates spindle pole movement via an Eg5-dependent mechanism.[8]

Binding with Xlp2

When bound to microtubules, TPX2 recruits a plus-end directed motor protein, Xlp2, a protein that is required in early mitosis and localizes to spindle poles, to microtubule minus ends of asters.[13][24][25] Like TPX2’s localization to microtubules, this recruitment is also RanGTP independent.[13][26]

Regulation of TPX2 in the cell cycle

Monitoring TPX2 gene mRNA expression during cell cycle progression in synchronized HeLa cells revealed that TPX2 expression is high in G2/M phase, decreases dramatically upon G1 phase entry, increases upon entry into S phase, and peaks again at the next G2/M phase.[27][10] This is correlated by results showing an increased stability of TPX2 in S-phase extracts compared to that of TPX2 in mitotic extracts, indicated by a significant increase in TPX2 half-life.[10] The drop in TPX2 is consistent with the drastic reorganization in structure and dynamics of the mitotic spindle.[28]

Overall, TPX2 has been shown through in vivo experiments to be regulated by the APC/CCdh1 pathway.[10] The instability and drop in TPX2 at mitotic exit is dependent on both the anaphase-promoting complex/cyclosome (APC/C) and an ubiquitin ligase integral in mitotic progression, along with APC/C's activator protein, Cdh1.[10][29] This is a result of TPX2 being bound directly by Cdh1, and not Cdc20 or any other substrate of APC/CCdh1, and designated for degradation by APC/C.[10] Moreover, the Cdh1-TPX2 binding interaction produces the TPX2 stability seen during mitosis up until mitotic exit: The amino-terminal region of Cdh1 (amino acids 1-125) can act as a dominant negative mutant when expressed in mammalian cells, stabilizing APC/CCdh1 substrates such as TPX2 by competitive binding.[10]

Role in the nucleus

When the cell is in interphase, because of its ability to bind to importin α and β, TPX2 has been found localized in the nucleus.[1][13] This has been proposed to be a physical mechanism by which proteins that operate in M phase are inactivated in interphase. TPX2 during M-phase accumulates at the poles of spindles in a “dynein-dynactin-dependent way.”[13][5] The mechanism of this localization currently remains unclear, but it is not RanGTP dependent despite its downfield position from RanGTP activity, as TPX2 in Xenopus laevis egg extracts have been shown to accumulate at the center of microtubule asters (after the addition of centrosomes, taxol, or DMSO) and bind to pure microtubules in the presence of importins.[15]

Though nuclear import of TPX2 is thought to sequester TPX2 away from cytoplasmic tubulin in order to solely prevent premature spindle assembly,[30][31] roles of nuclear TPX2 have recently been discovered. One of these roles is with the DNA damage response, where depletion of TPX2 in cells leads to a transient increase in γ-H2AX (the phosphorylated form of H2AX, the form that serves as a marker of DNA damage response amplification) levels in cells treated with ionizing radiation,[32] and overexpression of TPX2 leads to a decrease in the number of ionizing radiation-induced MDC1 foci and γ-H2AX levels.[32] This is supported by the discovery of TPX2 accumulation at DNA double strand breaks and association with the machinery of DNA damage response that controls the amplification of γ-H2AX.[32] However, the exact molecular mechanisms by which TPX2 impacts the ionizing radiation-dependent γ-H2AX levels still remains to be discovered.  Note that TPX2’s function in the DNA damage response is independent of its mitotic function, and is therefore independent of apoptosis.

When no ionizing radiation is present, TPX2 readily associates with the chromatin.[33] Interestingly, overexpression of TPX2 in these conditions produces abnormal DAPI staining patterns, where DAPI staining is more structured and compartmentalized than the typical uniformly-distributed DAPI staining in wild type cells.[33] Moreover, when TPX2 levels were depleted in unirradiated cells, no significant changes in γ-H2AX levels were found,[32] but the levels of H4K16ac, the acetylated form of H4K16 (a histone post-translationally modified during DNA damage response), decreased.[33] This decrease is unaffected by ionizing radiation, yet correlates with the decrease in γ-H2AX under such conditions. A result of this decrease is a defect in BP531 (p53 binding protein 1) recruitment to chromosomal breaks,[33] as recruitment is dependent on the acetylation status of H4K16.[34] As with TPX2 with regards to its impact on ionizing radiation-dependent γ-H2AX levels, the molecular mechanism by which TPX2 affects the acetylation status of H4K16 remains to be discovered.

Relevance in cancer

Because of its integral role in microtubule assembly and therefore mitosis, TPX2 is found to be overexpressed in different types of human cancers including hepatocellular carcinoma (HCC),[27] medullary thyroid cancer,[35] bladder carcinoma,[36] and estrogen receptor-positive metastatic breast cancer[37] and contributes to tumor growth and metastasis.[27] In HCC, TPX2 has been shown to be positively correlated with poor prognosis, metastasis, and recurrence.[38][39][40] Studies on TPX2 in HCC have also showed that TPX2 promotes tumoriogenesis and liver cancer cell growth by increasing tumor spheroid and diminishing cell growth inhibition, demonstrated by knocking out endogenous expression of TPX2 using TPX2 si-RNA.[27]

As a result, TPX2 has recently been a topic of interest for learning more about the relationship between mitotic errors and tumorigenesis, along with novel cancer therapies. So far, research on depleting TPX2 via TPX2 si-RNA in HCC cells in vitro has shown significant effects in diminishing cell motility and invasion (i.e. metastasis), along with diminishing proteins involved in the G1 to S phase transition.[27] Similar results have been shown with TPX2 depletion in esophageal cancer EC9706 cells, leading to reduced cancer cell growth and invasion ability,[41] and in cervical[42] and pancreatic cancer[43] with regards to reduced tumor growth using TPX2 si-RNA transfection.

In liver cancer cells, TPX2 depletion has been linked to increased genomic instability, resulting in multinucleation and DNA damage.[27] While many tumor cells in general accumulate mutations in genomic instability that enable them to have a growth advantage in tumor promotion and transformation,[44] high chromosomal instability can act as a tumor-suppressing mechanism by leading to cell death.[45][46] Therefore, the significant aneuploidy and genomic instability at mitotic division via TPX2 depletion can serve as a potential therapeutic target for cancer patients by eliminating highly proliferating cells.

References

  1. ↑ 1.0 1.1 1.2 Heidebrecht HJ, Buck F, Steinmann J, Sprenger R, Wacker HH, Parwaresch R (July 1997). "p100: a novel proliferation-associated nuclear protein specifically restricted to cell cycle phases S, G2, and M". Blood. 90 (1): 226–33. PMID 9207457.
  2. ↑ Zhang Y, Heidebrecht H, Rott A, Schlegelberger B, Parwaresch R (Jul 1999). "Assignment of human proliferation associated p100 gene (C20orf1) to human chromosome band 20q11.2 by in situ hybridization". Cytogenetics and Cell Genetics. 84 (3–4): 182–3. doi:10.1159/000015251. PMID 10393424.
  3. ↑ "Entrez Gene: TPX2 TPX2, microtubule-associated, homolog (Xenopus laevis)".
  4. ↑ Vos JW, Pieuchot L, Evrard JL, Janski N, Bergdoll M, de Ronde D, Perez LH, Sardon T, Vernos I, Schmit AC (October 2008). "The plant TPX2 protein regulates prospindle assembly before nuclear envelope breakdown". The Plant Cell. 20 (10): 2783–97. doi:10.1105/tpc.107.056796. PMC 2590745. PMID 18941054.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Trieselmann N, Armstrong S, Rauw J, Wilde A (December 2003). "Ran modulates spindle assembly by regulating a subset of TPX2 and Kid activities including Aurora A activation". Journal of Cell Science. 116 (Pt 23): 4791–8. doi:10.1242/jcs.00798. PMID 14600264.
  6. ↑ Sanchez-Pulido L, Perez L, Kuhn S, Vernos I, Andrade-Navarro MA (October 2016). "The C-terminal domain of TPX2 is made of alpha-helical tandem repeats". BMC Structural Biology. 16 (1): 17. doi:10.1186/s12900-016-0070-8. PMC 5080731. PMID 27782824.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 Alfaro-Aco R, Thawani A, Petry S (April 2017). "Structural analysis of the role of TPX2 in branching microtubule nucleation". The Journal of Cell Biology. 216 (4): 983–997. doi:10.1083/jcb.201607060. PMC 5379942. PMID 28264915.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Eckerdt F, Eyers PA, Lewellyn AL, Prigent C, Maller JL (April 2008). "Spindle pole regulation by a discrete Eg5-interacting domain in TPX2". Current Biology. 18 (7): 519–25. doi:10.1016/j.cub.2008.02.077. PMC 2408861. PMID 18372177.
  9. ↑ Ma N, Tulu US, Ferenz NP, Fagerstrom C, Wilde A, Wadsworth P (March 2010). "Poleward transport of TPX2 in the mammalian mitotic spindle requires dynein, Eg5, and microtubule flux". Molecular Biology of the Cell. 21 (6): 979–88. doi:10.1091/mbc.e09-07-0601. PMC 2836978. PMID 20110350.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 Stewart S, Fang G (December 2005). "Anaphase-promoting complex/cyclosome controls the stability of TPX2 during mitotic exit". Molecular and Cellular Biology. 25 (23): 10516–27. doi:10.1128/MCB.25.23.10516-10527.2005. PMC 1291225. PMID 16287863.
  11. ↑ Pfleger CM, Kirschner MW (March 2000). "The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1". Genes & Development. 14 (6): 655–65. PMID 10733526.
  12. ↑ Pfleger CM, Lee E, Kirschner MW (September 2001). "Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex". Genes & Development. 15 (18): 2396–407. doi:10.1101/gad.918201. PMID 11562349.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Wittmann T, Wilm M, Karsenti E, Vernos I (June 2000). "TPX2, A novel xenopus MAP involved in spindle pole organization". The Journal of Cell Biology. 149 (7): 1405–18. PMC 2175143. PMID 10871281.
  14. ↑ 14.0 14.1 14.2 Gruss OJ, Wittmann M, Yokoyama H, Pepperkok R, Kufer T, Silljé H, Karsenti E, Mattaj IW, Vernos I (November 2002). "Chromosome-induced microtubule assembly mediated by TPX2 is required for spindle formation in HeLa cells". Nature Cell Biology. 4 (11): 871–9. doi:10.1038/ncb870. PMID 12389033.
  15. ↑ 15.0 15.1 Gruss OJ, Vernos I (September 2004). "The mechanism of spindle assembly: functions of Ran and its target TPX2". The Journal of Cell Biology. 166 (7): 949–55. doi:10.1083/jcb.200312112. PMC 2172015. PMID 15452138.
  16. ↑ 16.0 16.1 Gruss OJ, Carazo-Salas RE, Schatz CA, Guarguaglini G, Kast J, Wilm M, Le Bot N, Vernos I, Karsenti E, Mattaj IW (January 2001). "Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity". Cell. 104 (1): 83–93. PMID 11163242.
  17. ↑ 17.0 17.1 17.2 Reid TA, Schuster BM, Mann BJ, Balchand SK, Plooster M, McClellan M, Coombes CE, Wadsworth P, Gardner MK (April 2016). "Suppression of microtubule assembly kinetics by the mitotic protein TPX2". Journal of Cell Science. 129 (7): 1319–28. doi:10.1242/jcs.178806. PMC 4852719. PMID 26869224.
  18. ↑ 18.0 18.1 18.2 Petry S, Groen AC, Ishihara K, Mitchison TJ, Vale RD (February 2013). "Branching microtubule nucleation in Xenopus egg extracts mediated by augmin and TPX2". Cell. 152 (4): 768–77. doi:10.1016/j.cell.2012.12.044. PMC 3680348. PMID 23415226.
  19. ↑ Petry S, Groen AC, Ishihara K, Mitchison TJ, Vale RD (February 2013). "Branching microtubule nucleation in Xenopus egg extracts mediated by augmin and TPX2". Cell. 152 (4): 768–77. doi:10.1016/j.cell.2012.12.044. PMC 3680348. PMID 23415226.
  20. ↑ 20.0 20.1 20.2 Bayliss R, Sardon T, Vernos I, Conti E (October 2003). "Structural basis of Aurora-A activation by TPX2 at the mitotic spindle". Molecular Cell. 12 (4): 851–62. PMID 14580337.
  21. ↑ Eyers PA, Maller JL (March 2004). "Regulation of Xenopus Aurora A activation by TPX2". The Journal of Biological Chemistry. 279 (10): 9008–15. doi:10.1074/jbc.M312424200. PMID 14701852.
  22. ↑ Bringmann H, Hyman AA (August 2005). "A cytokinesis furrow is positioned by two consecutive signals". Nature. 436 (7051): 731–4. doi:10.1038/nature03823. PMID 16079852.
  23. ↑ D'Avino PP, Savoian MS, Glover DM (April 2005). "Cleavage furrow formation and ingression during animal cytokinesis: a microtubule legacy". Journal of Cell Science. 118 (Pt 8): 1549–58. doi:10.1242/jcs.02335. PMID 15811947.
  24. ↑ Wittmann T, Boleti H, Antony C, Karsenti E, Vernos I (November 1998). "Localization of the kinesin-like protein Xklp2 to spindle poles requires a leucine zipper, a microtubule-associated protein, and dynein". The Journal of Cell Biology. 143 (3): 673–85. PMC 2148133. PMID 9813089.
  25. ↑ Boleti H, Karsenti E, Vernos I (January 1996). "Xklp2, a novel Xenopus centrosomal kinesin-like protein required for centrosome separation during mitosis". Cell. 84 (1): 49–59. PMID 8548825.
  26. ↑ Garrett S, Auer K, Compton DA, Kapoor TM (December 2002). "hTPX2 is required for normal spindle morphology and centrosome integrity during vertebrate cell division". Current Biology. 12 (23): 2055–9. PMID 12477396.
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 Hsu CW, Chen YC, Su HH, Huang GJ, Shu CW, Wu TT, Pan HW (2017). "Targeting TPX2 Suppresses the Tumorigenesis of Hepatocellular Carcinoma Cells Resulting in Arrested Mitotic Phase Progression and Increased Genomic Instability". Journal of Cancer. 8 (8): 1378–1394. doi:10.7150/jca.17478. PMC 5479243. PMID 28638452.
  28. ↑ Higuchi T, Uhlmann F (January 2005). "Stabilization of microtubule dynamics at anaphase onset promotes chromosome segregation". Nature. 433 (7022): 171–6. doi:10.1038/nature03240. PMC 2586334. PMID 15650742.
  29. ↑ Harper JW, Burton JL, Solomon MJ (September 2002). "The anaphase-promoting complex: it's not just for mitosis any more". Genes & Development. 16 (17): 2179–206. doi:10.1101/gad.1013102. PMID 12208841.
  30. ↑ Kahana JA, Cleveland DW (March 2001). "Cell cycle. Some importin news about spindle assembly". Science. 291 (5509): 1718–9. doi:10.1126/science.1059765. PMID 11253198.
  31. ↑ Schatz CA, Santarella R, Hoenger A, Karsenti E, Mattaj IW, Gruss OJ, Carazo-Salas RE (May 2003). "Importin alpha-regulated nucleation of microtubules by TPX2". The EMBO Journal. 22 (9): 2060–70. doi:10.1093/emboj/cdg195. PMID 12727873.
  32. ↑ 32.0 32.1 32.2 32.3 Neumayer G, Helfricht A, Shim SY, Le HT, Lundin C, Belzil C, Chansard M, Yu Y, Lees-Miller SP, Gruss OJ, van Attikum H, Helleday T, Nguyen MD (December 2012). "Targeting protein for xenopus kinesin-like protein 2 (TPX2) regulates γ-histone 2AX (γ-H2AX) levels upon ionizing radiation". The Journal of Biological Chemistry. 287 (50): 42206–22. doi:10.1074/jbc.M112.385674. PMC 3516765. PMID 23045526.
  33. ↑ 33.0 33.1 33.2 33.3 Neumayer G, Nguyen MD (2014-11-03). "TPX2 impacts acetylation of histone H4 at lysine 16: implications for DNA damage response". PloS One. 9 (11): e110994. doi:10.1371/journal.pone.0110994. PMC 4217740. PMID 25365214.
  34. ↑ van Attikum H, Gasser SM (May 2009). "Crosstalk between histone modifications during the DNA damage response". Trends in Cell Biology. 19 (5): 207–17. doi:10.1016/j.tcb.2009.03.001. PMID 19342239.
  35. ↑ Yang X, Liu G, Xiao H, Yu F, Xiang X, Lu Y, Li W, Liu X, Li S, Shi Y (July 2014). "TPX2 overexpression in medullary thyroid carcinoma mediates TT cell proliferation". Pathology Oncology Research. 20 (3): 641–8. doi:10.1007/s12253-014-9743-4. PMID 24488334.
  36. ↑ Yan L, Li S, Xu C, Zhao X, Hao B, Li H, Qiao B (December 2013). "Target protein for Xklp2 (TPX2), a microtubule-related protein, contributes to malignant phenotype in bladder carcinoma". Tumour Biology. 34 (6): 4089–100. doi:10.1007/s13277-013-1000-z. PMID 23873098.
  37. ↑ Geiger TR, Ha NH, Faraji F, Michael HT, Rodriguez L, Walker RC, Green JE, Simpson RM, Hunter KW (2014). "Functional analysis of prognostic gene expression network genes in metastatic breast cancer models". PloS One. 9 (11): e111813. doi:10.1371/journal.pone.0111813. PMC 4219783. PMID 25368990.
  38. ↑ Liang B, Jia C, Huang Y, He H, Li J, Liao H, Liu X, Liu X, Bai X, Yang D (August 2015). "TPX2 Level Correlates with Hepatocellular Carcinoma Cell Proliferation, Apoptosis, and EMT". Digestive Diseases and Sciences. 60 (8): 2360–72. doi:10.1007/s10620-015-3730-9. PMID 26025609.
  39. ↑ Liu Q, Yang P, Tu K, Zhang H, Zheng X, Yao Y, Liu Q (August 2014). "TPX2 knockdown suppressed hepatocellular carcinoma cell invasion via inactivating AKT signaling and inhibiting MMP2 and MMP9 expression". Chinese Journal of Cancer Research = Chung-Kuo Yen Cheng Yen Chiu. 26 (4): 410–7. doi:10.3978/j.issn.1000-9604.2014.08.01. PMC 4153921. PMID 25232213.
  40. ↑ Huang Y, Guo W, Kan H (October 2014). "TPX2 is a prognostic marker and contributes to growth and metastasis of human hepatocellular carcinoma". International Journal of Molecular Sciences. 15 (10): 18148–61. doi:10.3390/ijms151018148. PMC 4227208. PMID 25302620.
  41. ↑ Liu HC, Zhang GH, Liu YH, Wang P, Ma JF, Su LS, Li SL, Zhang L, Liu JW (September 2014). "TPX2 siRNA regulates growth and invasion of esophageal cancer cells". Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 68 (7): 833–9. doi:10.1016/j.biopha.2014.08.008. PMID 25239289.
  42. ↑ Jiang P, Shen K, Wang X, Song H, Yue Y, Liu T (June 2014). "TPX2 regulates tumor growth in human cervical carcinoma cells". Molecular Medicine Reports. 9 (6): 2347–51. doi:10.3892/mmr.2014.2106. PMID 24718984.
  43. ↑ Miwa T, Kokuryo T, Yokoyama Y, Yamaguchi J, Nagino M (July 2015). "Therapeutic potential of targeting protein for Xklp2 silencing for pancreatic cancer". Cancer Medicine. 4 (7): 1091–100. doi:10.1002/cam4.453. PMC 4529347. PMID 25914189.
  44. ↑ Pan HW, Ou YH, Peng SY, Liu SH, Lai PL, Lee PH, Sheu JC, Chen CL, Hsu HC (July 2003). "Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma". Cancer. 98 (1): 119–27. doi:10.1002/cncr.11487. PMID 12833464.
  45. ↑ McGranahan N, Burrell RA, Endesfelder D, Novelli MR, Swanton C (June 2012). "Cancer chromosomal instability: therapeutic and diagnostic challenges". EMBO Reports. 13 (6): 528–38. doi:10.1038/embor.2012.61. PMC 3367245. PMID 22595889.
  46. ↑ Holland AJ, Cleveland DW (June 2012). "Losing balance: the origin and impact of aneuploidy in cancer". EMBO Reports. 13 (6): 501–14. doi:10.1038/embor.2012.55. PMC 3367240. PMID 22565320.

Further reading

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