BUB1

Last updated
BUB1
BUB1 3E7E.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BUB1 , BUB1A, BUB1L, hBUB1 mitotic checkpoint serine/threonine kinase
External IDs OMIM: 602452; MGI: 1100510; HomoloGene: 37910; GeneCards: BUB1; OMA:BUB1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

699

12235

Ensembl

ENSG00000169679

ENSMUSG00000027379

UniProt

O43683

O08901

RefSeq (mRNA)

NM_001278616
NM_001278617
NM_004336

NM_001113179
NM_009772

RefSeq (protein)

NP_001265545
NP_001265546
NP_004327

NP_001106650
NP_033902

Location (UCSC) Chr 2: 110.64 – 110.68 Mb Chr 2: 127.64 – 127.67 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 (budding uninhibited by benzimidazoles 1) is an enzyme that in humans is encoded by the BUB1 gene. [5] [6]

Contents

Bub1 is a serine/threonine protein kinase first identified in genetic screens of Saccharomyces cerevisiae (baker's yeast). [7] The protein is bound to kinetochores and plays a key role in the establishment of the mitotic spindle checkpoint and chromosome congression. The mitotic checkpoint kinase is evolutionarily conserved in organisms as diverse as Saccharomyces cerevisiae and humans. Loss-of-function mutations or absence of Bub1 has been reported to result in aneuploidy, chromosomal instability (CIN) and premature senescence.

Structure

Bub1p comprises a conserved N-terminal region, a central non-conserved region and a C-terminal serine/threonine kinase domain. [8] The N-terminal region mediates binding of Hs-BUB1 to the mitotic kinetochore protein blinkin (a protein also commonly referred to as AF15q14). The latter interaction is essential for kinetochore localization of Bub1 and its function in cell cycle arrest induced by spindle assembly checkpoint (SAC) activation. [9] The crystal structure of human Bub1 revealed the presence of a N-terminal tetratricopeptide repeat (TPR) domain and a C-terminal kinase domain (residues 784–1085), adopting a canonical kinase fold with two lobes. The ATP binding and the catalytic sites are located at the interface of the two lobes. The N-terminal extension contains three β-strands and an α-helix, wrapping around the N lobe of the kinase domain. [10] : Figure1 

Subcellular location

In humans Bub1 accumulates gradually during G1 and S phase of the cell cycle, peaks at G2/M, and drops dramatically after mitosis. During prophase it localizes as one of the first proteins to the outer kinetochore, a process generally implicated in correct mitotic timing and checkpoint response to spindle damage. [11]

Function

The protein kinase Bub1 possesses versatile and distinct functions during the cell cycle, mainly in the SAC and chromosome alignment during metaphase. The protein's interaction network currently identified is similarly complex (see Figure 1).

Figure 1: Protein interaction network of human Bub1. Net image e kC3oSkmqG60N high res.png
Figure 1: Protein interaction network of human Bub1.

In eukaryotic cells the SAC serves as the central surveillance mechanism to ensure chromosomes are being passed on to the next generation in a reliable manner. Several components monitor correct bipolar attachment of microtubules to the kinetochore, presumably through detection of tension. Metaphase-to-anaphase transition is halted by the SAC as long as single kinetochores lack bipolar microtubule attachment, implying the need for a highly sensitive signaling pathway. Bub1 was claimed to be the master regulator of SAC formation and signaling. At least thirteen other proteins (Mad1, MAD2, MAD3/BubR1, BUB3, Mps1 etc.) are part of the check point, among which many have been identified to interact with Bub1.

Upon activation of the SAC Bub1 directly phosphorylates APC/C's coactivator Cdc20. [13] This phosphorylation event is probably achieved in complex with Bub3, which itself has been subjected to prior phosphorylation by Bub1. The phosphorylation of Cdc20 ultimately leads to decreased activity of APC/C which determines the metaphase-to-anaphase transition. In turn APC/C, now in complex with Cdh1, also acts on Bub1 by priming it for degradation to exit mitosis. [14]

In addition, kinetochore localization of Bub1 early during G2 or prophase is another aspect of SAC functioning. Bub1 is thought to serve as a platform recruiting other checkpoint and motor proteins as Mad1, Mad2, BubR1, CENP-E and PLK1 to the kinetochore. [15] [16] [17] Indeed, recent data suggest that the primary role of Bub1 during SAC activity is not Cdc20 phosphorylation but rather recruitment of BubR1, Mad1 and Mad2. [18]

Upon spindle damage Bub1 is also triggered to phosphorylate Mad1 [19] [20] leading to dissociation of the Mad1-Mad2 complex and thereby rendering Mad2 accessible for inhibition of Cdc20. Bub1 generally protects sister chromatide cohesion by enhancing Shugoshin protein (Sgo1) localization to the centromeric region. Through recruitment of the phosphatase PP2A Bub1 inhibits the action of PLK1, which removes Sgo1 from the centromere. [21] [22] [23] [24]

Contrarily PLK1 localization, as mentioned, also depends on the activity of Bub1. Studies in Xenopus extracts using RNAi or antibody depletion have indicated a crucial function of Bub1 in the organization of the inner centromere. Similarly to its role in kinetochore assembly, it recruits members of the chromosomal passenger complex (CPC) like Aurora B kinase, Survivin and INCENP. Direct phosphorylation of INCENP by Bub1 has been observed. [25]

RNAi mediated depletion of human Bub1 has indicated function in correct metaphase congression. Downstream targets identified are distinct kinetochore proteins as CENP-F, MCAK and the mentioned Sgo1. [18]

Implications in cancer

Disturbed mitotic checkpoints are a common feature of many human cancers. More precisely, mutations in the spindle checkpoint can lead to chromosomal instability and aneuploidy, a feature present in over 90% of all solid tumors. [26] Loss-of-function mutations or reduced gene expression of Bub1 have been identified in several human tumors as colon, esophageal, gastric, breast cancer and melanoma. [18] A correlation between Bub1 expression levels and the localization of tumors along with their severity was found. For instance, low Bub1 expression levels resulted in more sarcomas, lymphomas and lung tumors, whereas higher ones caused sarcomas and tumors in the liver. [27] Moreover, Bub1 has been identified as a target of the large T antigen of the SV-40 virus, possibly contributing to its potential for oncogenic transformation. [28] Indications for possible Bub1 involvement in tumorigenesis also derive from animal experiments, where mice with reduced Bub1 expression showed an increase in tumor susceptibility. [29] [30] In vitro knockdown of Bub1 in p53 impaired cells (e.g. HeLa cells) caused aneuploidy. [31] Whether aneuploidy alone is a sufficient driving cause during tumorigenesis or rather a mere consequence has been a matter of scientific debate.

Recently Bub1 has been identified as a negative regulator of CIMD. Depletion of Bub1 results in increased CIMD in order to avoid aneuploidy caused by reduced SAC functioning. The transcriptional activity of p73 is thereby inhibited via phosphorylation. Direct interaction between these two players has not been visualized so far, therefore molecules linking Bub1 and p73 are yet to be determined. [32] It has also been proposed that Bub1 binds p53 to prevent it from activating pro-apoptotic genes, therefore p53 is able to induce apoptosis when Bub1 is depleted. However, an interaction between p53 and Bub1 has not yet been shown while p53 binding BubR1 has been reported. [33]

See also

Related Research Articles

<span class="mw-page-title-main">Spindle apparatus</span> Feature of biological cell structure

In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

<span class="mw-page-title-main">Kinetochore</span> Protein complex that allows microtubules to attach to chromosomes during cell division

A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.

Mad2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer sensitivity to microtubule poisons. The human orthologues of Mad2 were first cloned in a search for human cDNAs that would rescue the microtubule poison-sensitivity of a yeast strain in which a kinetochore binding protein was missing. The protein was shown to be present at unattached kinetochores and antibody inhibition studies demonstrated it was essential to execute a block in the metaphase-to-anaphase transition in response to the microtubule poison nocodazole. Subsequent cloning of the Xenopus laevis orthologue, facilitated by the sharing of the human sequence, allowed for the characterization of the mitotic checkpoint in egg extracts.

<span class="mw-page-title-main">Aurora kinase A</span> Protein-coding gene in the species Homo sapiens

Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.

<span class="mw-page-title-main">Aurora kinase B</span> Protein

Aurora kinase B is a protein that functions in the attachment of the mitotic spindle to the centromere and in cytokinesis.

<span class="mw-page-title-main">CDC20</span> Protein-coding gene in humans

The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.

<span class="mw-page-title-main">BUB1B</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint serine/threonine-protein kinase BUB1 beta is an enzyme that in humans is encoded by the BUB1B gene. Also known as BubR1, this protein is recognized for its mitotic roles in the spindle assembly checkpoint (SAC) and kinetochore-microtubule interactions that facilitate chromosome migration and alignment. BubR1 promotes mitotic fidelity and protects against aneuploidy by ensuring proper chromosome segregation between daughter cells. BubR1 is proposed to prevent tumorigenesis.

<span class="mw-page-title-main">MAD2L1</span> Protein-coding gene in the species Homo sapiens

Mitotic spindle assembly checkpoint protein MAD2A is a protein that in humans is encoded by the MAD2L1 gene.

<span class="mw-page-title-main">CDC27</span> Protein-coding gene in humans

Cell division cycle protein 27 homolog is a protein that in humans is encoded by the CDC27 gene.

<span class="mw-page-title-main">NEK2</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase Nek2 is an enzyme that in humans is encoded by the NEK2 gene.

<span class="mw-page-title-main">NDC80</span> Protein-coding gene in the species Homo sapiens

Kinetochore protein NDC80 homolog is a protein that in humans is encoded by the NDC80 gene.

<span class="mw-page-title-main">Centromere protein E</span> Centromere- and microtubule-associated protein

Centromere-associated protein E is a protein that in humans is encoded by the CENPE gene.

<span class="mw-page-title-main">BUB3</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene.

<span class="mw-page-title-main">NUF2</span> Protein-coding gene in the species Homo sapiens

Kinetochore protein Nuf2 is a protein that in humans is encoded by the NUF2 gene.

<span class="mw-page-title-main">Aurora kinase C</span> Protein-coding gene in the species Homo sapiens

Aurora kinase C, also Serine/threonine-protein kinase 13 is an enzyme that in humans is encoded by the AURKC gene.

<span class="mw-page-title-main">Mad1</span>

Mad1 is a non-essential protein which in yeast has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homologues of Mad1 are conserved in eukaryotes from yeast to mammals.

Mitotic exit is an important transition point that signifies the end of mitosis and the onset of new G1 phase for a cell, and the cell needs to rely on specific control mechanisms to ensure that once it exits mitosis, it never returns to mitosis until it has gone through G1, S, and G2 phases and passed all the necessary checkpoints. Many factors including cyclins, cyclin-dependent kinases (CDKs), ubiquitin ligases, inhibitors of cyclin-dependent kinases, and reversible phosphorylations regulate mitotic exit to ensure that cell cycle events occur in correct order with fewest errors. The end of mitosis is characterized by spindle breakdown, shortened kinetochore microtubules, and pronounced outgrowth of astral (non-kinetochore) microtubules. For a normal eukaryotic cell, mitotic exit is irreversible.

<span class="mw-page-title-main">Tim J. Yen</span> American molecular biologist

Tim J. Yen is an American molecular biologist and cancer biologist. Yen held the rank of Professor and in 2023, became Emeritus at Fox Chase Cancer Center in Philadelphia, Pennsylvania. Yen is known for pioneering work in the field of mitosis.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000169679 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027379 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast)".
  6. ↑ Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (Mar 1998). "Mutations of mitotic checkpoint genes in human cancers". Nature. 392 (6673): 300–3. Bibcode:1998Natur.392..300C. doi:10.1038/32688. PMID   9521327. S2CID   4416376.
  7. ↑ Roberts BT, Farr KA, Hoyt MA (Dec 1994). "The Saccharomyces cerevisiae checkpoint gene BUB1 encodes a novel protein kinase". Molecular and Cellular Biology. 14 (12): 8282–91. doi:10.1128/mcb.14.12.8282. PMC   359367 . PMID   7969164.
  8. ↑ Bolanos-Garcia VM, Kiyomitsu T, D'Arcy S, Chirgadze DY, Grossmann JG, Matak-Vinkovic D, Venkitaraman AR, Yanagida M, Robinson CV, Blundell TL (Jan 2009). "The crystal structure of the N-terminal region of BUB1 provides insight into the mechanism of BUB1 recruitment to kinetochores". Structure. 17 (1): 105–16. doi:10.1016/j.str.2008.10.015. PMC   2683949 . PMID   19141287.
  9. ↑ Kiyomitsu T, Obuse C, Yanagida M (Nov 2007). "Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1". Developmental Cell. 13 (5): 663–76. doi: 10.1016/j.devcel.2007.09.005 . PMID   17981135.
  10. ↑ PDB: 3E7E ​; Kang J, Yang M, Li B, Qi W, Zhang C, Shokat KM, Tomchick DR, Machius M, Yu H (November 2008). "Structure and substrate recruitment of the human spindle checkpoint kinase Bub1". Mol. Cell. 32 (3): 394–405. doi:10.1016/j.molcel.2008.09.017. PMC   2644263 . PMID   18995837.
  11. ↑ UniProt: O43683
  12. ↑ "BUB1 protein (Homo sapiens) - STRING interaction network". STRING (Search Tool for the Retrieval of Interacting Genes/Proteins). European Molecular Biology Laboratory. Archived from the original on 2011-07-18. Retrieved 2010-06-29.
  13. ↑ Tang Z, Shu H, Oncel D, Chen S, Yu H (Nov 2004). "Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint". Molecular Cell. 16 (3): 387–97. doi: 10.1016/j.molcel.2004.09.031 . PMID   15525512.
  14. ↑ Qi W, Yu H (Feb 2007). "KEN-box-dependent degradation of the Bub1 spindle checkpoint kinase by the anaphase-promoting complex/cyclosome". The Journal of Biological Chemistry. 282 (6): 3672–9. doi: 10.1074/jbc.M609376200 . PMID   17158872.
  15. ↑ Sharp-Baker H, Chen RH (Jun 2001). "Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity". The Journal of Cell Biology. 153 (6): 1239–50. doi:10.1083/jcb.153.6.1239. PMC   2192030 . PMID   11402067.
  16. ↑ Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS (Mar 2004). "Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression". Journal of Cell Science. 117 (Pt 8): 1577–89. doi: 10.1242/jcs.01006 . PMID   15020684.
  17. ↑ Meraldi P, Draviam VM, Sorger PK (Jul 2004). "Timing and checkpoints in the regulation of mitotic progression". Developmental Cell. 7 (1): 45–60. doi: 10.1016/j.devcel.2004.06.006 . PMID   15239953.
  18. 1 2 3 Klebig C, Korinth D, Meraldi P (Jun 2009). "Bub1 regulates chromosome segregation in a kinetochore-independent manner". The Journal of Cell Biology. 185 (5): 841–58. doi:10.1083/jcb.200902128. PMC   2711590 . PMID   19487456.
  19. ↑ Yu H (Dec 2002). "Regulation of APC-Cdc20 by the spindle checkpoint". Current Opinion in Cell Biology. 14 (6): 706–14. doi:10.1016/S0955-0674(02)00382-4. PMID   12473343.
  20. ↑ Zhang Y, Lees E (Aug 2001). "Identification of an overlapping binding domain on Cdc20 for Mad2 and anaphase-promoting complex: model for spindle checkpoint regulation". Molecular and Cellular Biology. 21 (15): 5190–9. doi:10.1128/MCB.21.15.5190-5199.2001. PMC   87243 . PMID   11438673.
  21. ↑ Tang Z, Sun Y, Harley SE, Zou H, Yu H (Dec 2004). "Human Bub1 protects centromeric sister-chromatid cohesion through Shugoshin during mitosis". Proceedings of the National Academy of Sciences of the United States of America. 101 (52): 18012–7. Bibcode:2004PNAS..10118012T. doi: 10.1073/pnas.0408600102 . PMC   539817 . PMID   15604152.
  22. ↑ Tang Z, Shu H, Qi W, Mahmood NA, Mumby MC, Yu H (May 2006). "PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation". Developmental Cell. 10 (5): 575–85. doi: 10.1016/j.devcel.2006.03.010 . PMID   16580887.
  23. ↑ Jang YJ, Ji JH, Choi YC, Ryu CJ, Ko SY (Jan 2007). "Regulation of Polo-like kinase 1 by DNA damage in mitosis. Inhibition of mitotic PLK-1 by protein phosphatase 2A". The Journal of Biological Chemistry. 282 (4): 2473–82. doi: 10.1074/jbc.M605480200 . PMID   17121863.
  24. ↑ Pouwels J, Kukkonen AM, Lan W, Daum JR, Gorbsky GJ, Stukenberg T, Kallio MJ (Jul 2007). "Shugoshin 1 plays a central role in kinetochore assembly and is required for kinetochore targeting of Plk1". Cell Cycle. 6 (13): 1579–85. doi: 10.4161/cc.6.13.4442 . PMID   17617734.
  25. ↑ Boyarchuk Y, Salic A, Dasso M, Arnaoutov A (Mar 2007). "Bub1 is essential for assembly of the functional inner centromere". The Journal of Cell Biology. 176 (7): 919–28. doi:10.1083/jcb.200609044. PMC   2064078 . PMID   17389228.
  26. ↑ Williams BR, Amon A (Jul 2009). "Aneuploidy: cancer's fatal flaw?". Cancer Research. 69 (13): 5289–91. doi:10.1158/0008-5472.CAN-09-0944. PMC   2917070 . PMID   19549887.
  27. ↑ King RW (Sep 2008). "When 2+2=5: the origins and fates of aneuploid and tetraploid cells". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1786 (1): 4–14. doi:10.1016/j.bbcan.2008.07.007. PMC   2581926 . PMID   18703117.
  28. ↑ Hein J, Boichuk S, Wu J, Cheng Y, Freire R, Jat PS, Roberts TM, Gjoerup OV (Jan 2009). "Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding". Journal of Virology. 83 (1): 117–27. doi:10.1128/JVI.01515-08. PMC   2612341 . PMID   18922873.
  29. ↑ Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM (Oct 2007). "Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis". The Journal of Cell Biology. 179 (2): 255–67. doi:10.1083/jcb.200706015. PMC   2064762 . PMID   17938250.
  30. ↑ Schliekelman M, Cowley DO, O'Quinn R, Oliver TG, Lu L, Salmon ED, Van Dyke T (Jan 2009). "Impaired Bub1 function in vivo compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis". Cancer Research. 69 (1): 45–54. doi:10.1158/0008-5472.CAN-07-6330. PMC   4770788 . PMID   19117986.
  31. ↑ Williams GL, Roberts TM, Gjoerup OV (Jul 2007). "Bub1: escapades in a cellular world". Cell Cycle. 6 (14): 1699–704. doi: 10.4161/cc.6.14.4493 . PMID   17643075.
  32. ↑ Kitagawa K, Niikura Y (Apr 2008). "Caspase-independent mitotic death (CIMD)". Cell Cycle. 7 (8): 1001–5. doi: 10.4161/cc.7.8.5720 . PMID   18414023.
  33. ↑ Beeharry N, Yen TJ (Apr 2009). "p53-dependent apoptosis in response to spindle damage is linked to loss of Bub1". Cancer Biology & Therapy. 8 (7): 645–7. doi: 10.4161/cbt.8.7.8140 . PMID   19270499.
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