v-Src-driven transformation is due to chromosome abnormalities but not Src-mediated growth signaling

Honda, Takeshi; Morii, Mariko; Nakayama, Yuji; Suzuki, Ko; Yamaguchi, Noritaka; Yamaguchi, Naoto

doi:10.1038/s41598-018-19599-1

Cited by 11 publications

(8 citation statements)

References 43 publications

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“…The chromosome instability generates genetic diversity, and cells capable of adapting to growth-suppressive conditions by anti-cancer drugs or cells gaining metastatic ability can be selected (7). Indeed, we recently reported that v-Src-driven transformation is attributable to chromosomal abnormalities (45). It is noteworthy that Csk knockdown can induce mitotic slippage, similar to v-Src expression, suggesting that increased Src kinase activity can attenuate SAC and cause mitotic slippage.…”

Section: V-src Induces Mitotic Slippage Through Cdk1 Phosphorylationmentioning

confidence: 99%

The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1

Horiuchi

Kuga

Saito

et al. 2018

Journal of Biological Chemistry

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The nonreceptor tyrosine kinase v-Src is an oncogene first identified in Rous sarcoma virus. The oncogenic effects of v-Src have been intensively studied; however, its effects on chromosomal integrity are not fully understood. Here, using HeLa S3/v-Src cells having inducible v-Src expression, we found that v-Src causes mitotic slippage in addition to cytokinesis failure, even when the spindle assembly checkpoint is not satisfied because of the presence of microtubule-targeting agents. v-Src's effect on mitotic slippage was also observed in cells after a knockdown of C-terminal Src kinase (Csk), a protein-tyrosine kinase that inhibits Src-family kinases and was partially inhibited by PP2, an Src-family kinase inhibitor. Proteomic analysis and kinase assay revealed that v-Src phosphorylates cyclin-dependent kinase 1 (Cdk1) at Tyr-15. This phosphorylation attenuated Cdk1 kinase activity, resulting in a decrease in the phosphorylation of Cdk1 substrates. Furthermore, v-Src-induced mitotic slippage reduced the sensitivity of the cells to microtubule-targeting agents, and cells that survived the microtubule-targeting agents exhibited polyploidy. These results suggest that v-Src causes mitotic slippage by attenuating Cdk1 kinase activity via direct phosphorylation of Cdk1 at Tyr-15. On the basis of these findings, we propose a model for v-Src-induced oncogenesis, in which v-Src-promoted mitotic slippage due to Cdk1 phosphorylation generates genetic diversity via abnormal cell division of polyploid cells and also increases the tolerance of cancer cells to microtubule-targeting agents.

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Section: V-src Induces Mitotic Slippage Through Cdk1 Phosphorylationmentioning

confidence: 99%

The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1

Horiuchi

Kuga

Saito

et al. 2018

Journal of Biological Chemistry

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“…HeLa S3/TR cells inducibly expressing Fyn (HeLa S3/TR/Fyn) were generated using HeLa S3/TR cells, which constitutively express the tetracycline repressor (TR) 24 , and pcDNA4/TO/neo/Fyn, as previously described 22 . Strictly controlled inducible expression is advantageous because protein expression levels may be adjusted to an appropriate amount 24 , 26 . SFK-mediated tyrosine phosphorylation was assessed using 20 µM PP2 (Sigma-Aldrich), 10 µM SU6656, 0.6 µM MLN8237 (Selleck Chemicals), and 10 µM sunitinib (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…(i) (G 1 /S phase) Cells were cultured for 20–24 h with 4 mM thymidine (thymidine block) 55 . Alternatively, cells were cultured with 4 mM thymidine for 20 h, transferred into fresh medium for 9 h, and then cultured with 4 mM thymidine (double thymidine block) for 15 h 26 . (ii) (Late G 2 phase) Cells arrested in the G 1 /S phase by the thymidine block were released for 9 h, and then treated with 9 μM of the Cdk1 inhibitor RO-3306 for 4–9 h 22 .…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, c-Src promotes proper spindle orientation 22 , while Fyn increases the rate of microtubule polymerization and accelerates mitotic progression 23 . v-Src, a viral oncogenic derivative of the proto-oncogene c-Src, has been shown to partly inhibit cell proliferation through the aberrant localization of Mklp1 and Aurora B, resulting in mitotic slippage, binucleation, and chromosome abnormalities 24 – 26 . The membrane attachment of SFKs via their lipid modifications during the period from prophase to anaphase plays a protective role against chromosome missegregation 27 .…”

Section: Introductionmentioning

confidence: 99%

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Src-mediated tyrosine phosphorylation of PRC1 and kinastrin/SKAP on the mitotic spindle

Morii

Kubota

Hasegawa

et al. 2021

Sci Rep

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Src-family tyrosine kinases (SFKs) play important roles in a number of signal transduction events during mitosis, such as spindle formation. A relationship has been reported between SFKs and the mitotic spindle; however, the underlying mechanisms remain unclear. We herein demonstrated that SFKs accumulated in the centrosome region at the onset of mitosis. Centrosomal Fyn increased in the G2 phase in a microtubule polymerization-dependent manner. A mass spectrometry analysis using mitotic spindle preparations was performed to identify tyrosine-phosphorylated substrates. Protein regulator of cytokinesis 1 (PRC1) and kinastrin/small kinetochore-associated protein (kinastrin/SKAP) were identified as SFK substrates. SFKs mainly phosphorylated PRC1 at Tyr-464 and kinastrin at Tyr-87. Although wild-type PRC1 is associated with microtubules, phosphomimetic PRC1 impaired the ability to bind microtubules. Phosphomimetic kinastrin at Tyr-87 also impaired binding with microtubules. Collectively, these results suggest that tyrosine phosphorylation of PRC1 and kinastrin plays a role in their delocalization from microtubules during mitosis.

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“…v‐Src promotes cell growth signals such as activation of MAPK/ERK pathway and CDK‐cyclin complexes. However, we showed that the inducible expression of v‐Src inhibits cell proliferation along with up‐regulation of the CDK inhibitor p21 7,8 . Given that v‐Src causes mitotic defects such as chromosome bridge formation and brings about colony formation at a low frequency, v‐Src‐mediated cell transformation may be attributed to stochastic results of chromosomal abnormalities 7‐9 .…”

Section: Introductionmentioning

confidence: 93%

The tyrosine kinase v‐Src modifies cytotoxicities of anticancer drugs targeting cell division

Yuki

Hagino

Ueno

et al. 2021

J Cellular Molecular Medi

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v‐Src oncogene causes cell transformation through its strong tyrosine kinase activity. We have revealed that v‐Src‐mediated cell transformation occurs at a low frequency and it is attributed to mitotic abnormalities‐mediated chromosome instability. v‐Src directly phosphorylates Tyr‐15 of cyclin‐dependent kinase 1 (CDK1), thereby causing mitotic slippage and reduction in Eg5 inhibitor cytotoxicity. However, it is not clear whether v‐Src modifies cytotoxicities of the other anticancer drugs targeting cell division. In this study, we found that v‐Src restores cancer cell viability reduced by various microtubule‐targeting agents (MTAs), although v‐Src does not alter cytotoxicity of DNA‐damaging anticancer drugs. v‐Src causes mitotic slippage of MTAs‐treated cells, consequently generating proliferating tetraploid cells. We further demonstrate that v‐Src also restores cell viability reduced by a polo‐like kinase 1 (PLK1) inhibitor. Interestingly, treatment with Aurora kinase inhibitor strongly induces cell death when cells express v‐Src. These results suggest that the v‐Src modifies cytotoxicities of anticancer drugs targeting cell division. Highly activated Src‐induced resistance to MTAs through mitotic slippage might have a risk to enhance the malignancy of cancer cells through the increase in chromosome instability upon chemotherapy using MTAs.

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v-Src-driven transformation is due to chromosome abnormalities but not Src-mediated growth signaling

Cited by 11 publications

References 43 publications

The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1

The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1

Src-mediated tyrosine phosphorylation of PRC1 and kinastrin/SKAP on the mitotic spindle

The tyrosine kinase v‐Src modifies cytotoxicities of anticancer drugs targeting cell division

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