Lack of PTEN sequesters CHK1 and initiates genetic instability

Puc, Janusz; Keniry, Megan; Li, Hong Shen; Pandita, Tej K.; Choudhury, Atish D.; Memeo, Lorenzo; Mansukhani, Mahesh; Murty, Vundavalli V.; Gaciong, Zbigniew; Meek, Sarah; Piwnica‐Worms, Helen; Hibshoosh, Hanina; Parsons, Ramon

doi:10.1016/j.ccr.2005.01.009

Cited by 297 publications

(283 citation statements)

References 59 publications

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“…The subcellular localization of Chk1 was controversial, with centrosomes, nuclear, cytoplasm and kinetochores being considered as possible sites. 25,[31][32][33] We find that Chk1 is localized in the germinal vesicle and to the spindle from pro-MI to MII stages, 6 -Chk1 mRNA and arrested in M2 medium containing 2.5 μM milrinone for 2 h before being collected for western blot. (B) Change of myc was calculated by gray-scale analysis using the software Quantity one (Bio-Rad).…”

Section: Discussionmentioning

confidence: 89%

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

et al. 2012

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Section: Discussionmentioning

confidence: 89%

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

et al. 2012

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“…The leukemic cells assayed here were p53 ¡/¡ and/or pten ¡/¡ , which have intrinsic genomic instability 32,33,46 and are permissive for polyploidisation. 34 The observed increase in aneuploidy induced by Erk5 silencing could result from initial dNTP misincorporation due to nucleotide imbalance, which may produce DNA damage and chromosomal instability, 29 presumably through mitotic nondisjunction.…”

Section: Discussionmentioning

confidence: 99%

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

et al. 2015

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An adequate supply of nucleotides is essential for accurate DNA replication, and inappropriate deoxyribonucleotide triphosphate (dNTP) concentrations can lead to replication stress, a common source of DNA damage, genomic instability and tumourigenesis. Here, we provide evidence that Erk5 is necessary for correct nucleotide supply during erythroid development. Mice with Erk5 knockout in the haematopoietic lineage showed impaired erythroid development in bone marrow, accompanied by altered dNTP levels and increased DNA mutagenesis in erythroid progenitors as detected by exome sequencing. Moreover, Erk5-depleted leukemic Jurkat cells presented a marked sensitivity to thymidine-induced S phase stalling, as evidenced by increased H2AX phosphorylation and apoptosis. The increase in thymidine sensitivity correlated with a higher dTTP/dCTP ratio. These results indicate that Erk5 is necessary to maintain the balance of nucleotide levels, thus preventing dNTP misincorporation and DNA damage in proliferative erythroid progenitors and leukemic Jurkat T cells.

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“…Despite these advances in delineating BBC, the molecular lesions and oncogenic signaling pathways that drive BBC and the precise oncogenic consequences of BRCA1-mediated basal-like tumorigenesis are incompletely known. The phosphatidylinositol 3-kinase (PI3K) pathway is a potent oncogenic signaling cascade that promotes cell transformation, proliferation, migration, angiogenesis and genomic instability; inhibits apoptosis; maintains stem cell compartments; and is associated with poor prognosis in carcinoma [11][12][13][14] . PTEN is the crucial tumor suppressor in this pathway because it catalyzes the precise opposite reaction to PI3K, thereby inhibiting downstream signaling 12 .…”

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confidence: 99%

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

et al. 2007

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Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis [1][2][3] . Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype [3][4][5] ; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent Correspondence should be addressed to R.P. (rep15@columbia.edu). 14 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS L.H.S., S.K.G.-S., R.P. and Å.B conceived and designed the study; L.H.S., S.K.G.-S., J.S., G.J., K.H., S.K., J.V.-C., H.O., T.S., L.M., S.P.E., H.H., R.P. and Å.B. collected the samples; L.H.S., K.L., M.J., L.M., T.L., M.S., J.I. and H.H. performed and analyzed immunohistochemistry experiments; L.H.S. and C.P. designed and performed methylation analyses; L.H.S., C.P., M.M. and K.H. performed nucleotide sequencing experiments; L.H.S., J.S., G.J. and K.H. performed and analyzed aCGH experiments; L.H.S., M.M.P., S.S. and V.V.V.S.M. designed and performed FISH experiments; L.H.S., S.K.G.-S. and M.K. performed statistical analyses; R.P. and Å.B. supervised the study; and L.H.S. wrote the paper with assistance from R.P. and Å.B. and input from all coauthors.Note: Supplementary information is available on the Nature Genetics website. [1][2][3][4][5] . Of these, basal-like breast cancer (BBC) comprises 10-20% of all breast cancer and is one of the subtypes with the worst prognosis 2-5 . The term BBC was coined because these tumors express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland, such as CK5, CK14 and CK17 (refs. 1,3,5 ). In addition to having characteristic cytokeratin expression, BBCs are highly proliferative, poorly differentiated and genomically unstable, and they pose clinical challenges because they rarely express the three most common therapeutically targeted 'Achilles' heels' of breast cancer: the estrogen receptor (ER), progesterone receptor and HER2 receptor (refs. 1,3,5,7 ).Intriguingly, breast tumors initiated by an inherited mutation of BRCA1 are nearly always basal-like 3,5 . BRCA1 dysfunction is thought to be tumorigenic primarily owing to defective BRCA1-dependent DSB repair, which precipitates an accumulation of secondary mutations 10 ; however, only general genomic patterns at relatively low resolution have been described (reviewed in ref. 5 ). Despite these advances in delineating BBC, the molecu...

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Lack of PTEN sequesters CHK1 and initiates genetic instability

Cited by 297 publications

References 59 publications

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

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