Molecular analyses of the mitotic checkpoint componentshsMAD2, hBUB1 andhBUB3 in human cancer

Hernando, Eva; Orlow, Irene; Liberal, Vasco; Nohales, Gloria; Benezra, Robert; Cordon‐Cardo, Carlos

doi:10.1002/1097-0215(20010720)95:4<223::aid-ijc1038>3.0.co;2-l

Cited by 93 publications

(62 citation statements)

References 32 publications

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“…The types of sequence variations of p31 comet found in hepatocellular carcinoma tissues and cell lines was summarized (Table 2), three with amino acid substitution and one without amino acid change. The previous reports that Mad2 mutation frequency is extremely low (Takahashi et al, 1999;Gemma et al, 2001;Hernando et al, 2001), together with our present findings illustrate a notion that a circuit of p31 comet and Mad2 may not contribute to the formation of aneuploidy and tetraploidy found in human hepatocellular carcinoma.…”

Section: Mutation Of P31 Comet Gene In Human Hepatocellular Carcinomasupporting

confidence: 88%

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Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma

Yun

Kim²,

Park³

et al. 2007

Exp Mol Med

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Failure of mitotic checkpoint machinery leads to the chromosomal missegregation and nuclear endoreduplication, thereby driving the emergence of aneuploidy and tetraploidy population. Although abnormal nuclear ploidy and the resulting impairment of mitotic checkpoint function are typical physiological event leading to human hepatocellular carcinoma, any mutational change of mitotic checkpoint regulators has not yet been discovered. Therefore, we investigated the mutation of p31 comet , a recently identified mitotic checkpoint regulator, in human hepatocellular carcinoma. Of 51 human hepatocellular carcinoma tissue and 6 cell lines tested, five samples exhibited nucleotide sequence variations dispersed on four sites within the entire coding sequence. Among these sites with sequence substitutions, three were found to be missense mutation accompanied with amino acid change but one was a silent mutation. Of these sequence substitutions, two were present in both tumor and non-tumor liver tissues, suggesting the possibility of polymorphism. The present findings indicate that p31 comet does not have an impact on the formation of aneuploidy and tetraploidy found in human hepatocellular carcinoma.

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Section: Mutation Of P31 Comet Gene In Human Hepatocellular Carcinomasupporting

confidence: 88%

“…However, recent reports studying the mutation or expression of Mad2 showed that its defect was not a key factor in inducing tumorigenesis of various types of human tumors. Mutation of human Mad2 gene is very rare in breast, liver, lung and bladder cancers (Takahashi et al, 1999;Gemma et al, 2001;Hernando et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma

Yun

Kim²,

Park³

et al. 2007

Exp Mol Med

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“…Obvious candidate genes that might be involved in causing CIN in cancer are the spindle checkpoint genes, but these appear to be rarely inactivated by mutation in human cancer (Cahill et al, 1998;Nomoto et al, 1999;Takahashi et al, 1999;Hernando et al, 2001;Masuda and Takahashi, 2002). However, partial downregulation of spindle checkpoint genes including MAD1, MAD2, BUB1 and BUBR1 has been observed in cancer cells (Li and Benezra, 1996;Shichiri et al, 2002;Wang et al, 2002).…”

Section: Partial Downregulation Of Spindle Checkpoint In Human Cancermentioning

confidence: 99%

“…Indeed, defects in the spindle checkpoint are frequently found in various types of human cancer including lung, breast, ovarian, colon and hepatocellular tumors and these defects are associated with CIN and aneuploidy (Cahill et al, 1998;Takahashi et al, 1999;Masuda and Takahashi, 2002;Shichiri et al, 2002). While spindle checkpoint defects are frequent, spindle checkpoint genes appear to be rarely altered in human tumors (Cahill et al, 1998;Nomoto et al, 1999;Hernando et al, 2001). Instead, downregulated expression of spindle checkpoint genes might contribute to a deactivated spindle checkpoint in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol

et al. 2005

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The mitotic spindle assembly checkpoint ensures proper chromosome segregation during mitosis by inhibiting the onset of anaphase until all kinetochores are attached to the mitotic spindle and tension across the kinetochores is generated. Here, we report that the stable partial downregulation of the spindle checkpoint gene MAD1, which is observed in human cancer, leads to a functional inactivation of the spindle checkpoint resulting in gross aneuploidy. Interestingly, although Mad1 is thought to act as a kinetochore based activator of Mad2 during checkpoint activation, we show that normal levels of Mad2, but not of Mad1, are required for preventing premature sister chromatid separation and for maintaining the timing of an undisturbed mitosis, suggesting a Mad1 independent function of Mad2 that operates independent of its checkpoint function. Most significantly, a partial repression of either MAD1 or MAD2 confers resistance to nocodazole, a drug that inhibits microtubule attachment. In contrast, sensitivity to clinically relevant drugs like taxol or monastrol that inhibit the generation of tension across kinetochores is not modulated by partial downregulation of MAD1, suggesting a functional bifurcation of spindle checkpoint dependent apoptotic pathways.

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“…1,8 Potential candidates for the induction of aneuploidy other than hSecurin or the sister-chromatid separation pathway include members of the mitotic spindle checkpoint such as the BUB and MAD genes, which have been found to be mutated in some malignancies, albeit at a low frequency. [34][35][36] However, aneuploidy also occurs despite a functioning spindle checkpoint. 37 Hence, this may not be the major pathway leading to aberrant chromosome numbers.…”

Section: Discussionmentioning

confidence: 99%

High expression of the sister-chromatid separation regulator and proto-oncogene hSecurin occurs in a subset of myeloid leukaemias but is not implicated in the pathogenesis of aneuploidy

et al. 2003

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High expression of the sister-chromatid separation regulator and proto-oncogene hSecurin occurs in a subset of myeloid leukaemias but is not implicated in the pathogenesis of aneuploidy Aneuploidy is considered to play an important role in the pathogenesis of malignancies. We were interested whether abnormalities of the sister-chromatid separation regulator and proto-oncogene hSecurin occurred in myeloid leukaemias, and whether such abnormalities correlated with aneuploidy. The expression of hSecurin was assessed by real-time quantitative PCR in samples from patients with acute myeloid leukaemia (AML, n ¼ 70), chronic myeloid leukaemia (CML) in chronic phase (CP, n ¼ 20) or blast phase (BP, n ¼ 12), and granulocytes as well as mononuclear cells (MNCs) from healthy donors (n ¼ 21). Median hSecurin expression in AML with normal karyotypes was not significantly different from AML showing aneuploidy, CML BP or cells from healthy donors. However, hSecurin expression in CML CP was significantly increased compared to AML with normal karyotypes (1.82-fold; Po0.001), CML BP (3.18-fold; Po0.001), MNCs (3.17-fold; Po0.001) and granulocytes (2.69 fold; Po0.001) from healthy donors. Mutations in the coding region of hSecurin were not detected. These results do not support a major role of hSecurin in the development of aneuploidy in myeloid leukaemias. However, high expression of hSecurin may be of pathogenetic relevance in a subset of patients with regard to its potential to stimulate angiogenesis and to interact with the DNA-damage response pathway.

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Molecular analyses of the mitotic checkpoint componentshsMAD2, hBUB1 andhBUB3 in human cancer

Cited by 93 publications

References 32 publications

Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma

Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma

Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol

High expression of the sister-chromatid separation regulator and proto-oncogene hSecurin occurs in a subset of myeloid leukaemias but is not implicated in the pathogenesis of aneuploidy

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