Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle.

Watanabe, Naoko; Broome, Martin A.; Hunter, Tony

doi:10.1002/j.1460-2075.1995.tb07180.x

Cited by 403 publications

(364 citation statements)

References 82 publications

(67 reference statements)

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“…First, we checked the phosphorylation status of CDC2, which reflects its activity in vivo, in PKC412-treated AML cell lines. As shown in Figure 3a, CDC2 was heavily phosphorylated at tyrosine-15, an ATPbinding site critical for the kinase function of CDC2 (Watanabe et al, 1995), in untreated MOLM13 and MV4-11 cells. In contrast, CDC2-tyrosine 15 phosphorylation was not prominent in untreated THP-1 and U937 cells.…”

Section: Mv4-11 Molm13mentioning

confidence: 89%

“…We obtained evidence suggesting that FLT3 mutation-dependent responses to PKC412 T Odgerel et al the cell cycle effect is mediated through the modulation of CDC2 activity by PKC412. The kinase activity of CDC2 is regulated by the opposing effects of specific kinases (Myt-1 and Wee1) and a specific phosphatase (CDC25c) on tyrosine-15, an ATP-binding site of CDC2 (Galaktionov et al, 1995;Watanabe et al, 1995). In untreated AML cell lines harboring FLT3-ITD, CDC2 was found to be at least partially inactivated by phosphorylation at tyrosine-15.…”

Section: Discussionmentioning

confidence: 99%

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The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

et al. 2007

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PKC412 is a staurosporine derivative that inhibits several protein kinases including FLT3, and is highly anticipated as a novel therapeutic agent for acute myeloblastic leukemia (AML) carrying FLT3 mutations. In this study, we show that PKC412 exerts differential cell cycle effects on AML cells depending on the presence of FLT3 mutations. PKC412 elicits massive apoptosis without markedly affecting cell cycle patterns in AML cell lines with FLT3 mutations (MV4-11 and MOLM13), whereas it induces G 2 arrest but not apoptosis in AML cell lines without FLT3 mutations (THP-1 and U937). In MV4-11 and MOLM13 cells, PKC412 inactivates Myt-1 and activates CDC25c, leading to the activation of CDC2. Activated CDC2 phosphorylates Bad at serine-128 and facilitates its translocation to the mitochondria, where Bad triggers apoptosis. In contrast, PKC412 inactivates CDC2 by inducing serine-216 phosphorylation and subsequent cytoplasmic sequestration of CDC25c in THP-1 and U937 cells. As a result, cells are arrested in the G 2 phase of the cell cycle, but do not undergo apoptosis because Bad is not activated. The FLT3 mutationdependent differential cell cycle effect of PKC412 is considered an important factor when PKC412 is combined with cell cycle-specific anticancer drugs in the treatment of cancer and leukemia.

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Section: Mv4-11 Molm13mentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

et al. 2007

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“…Interestingly, 2 of the cancer-related genes in clusters 1A and 7A are regulated in a way which is not consistent with data from the literature. The tyrosine kinase WEE1 (cluster 1A, A01k), which plays a role in inhibiting mitosis before M phase by phosphorylating cyclin B1-Cdc2, 47 appears to be more strongly expressed in cancers compared to CIN. Likewise, the tyrosine kinase receptor erbB3 (cluster 7A, A14d), which is frequently overexpressed in human cancer, 48 was more weakly expressed in cancer vs. CIN3 biopsies.…”

Section: Discussionmentioning

confidence: 99%

Detection of cancer‐related gene expression profiles in severe cervical neoplasia

Sopov

Magbagbeolu

et al. 2004

Intl Journal of Cancer

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The molecular signatures of 20 severe cervical intraepithelial neoplasia (CIN3) cases and 10 cervical squamous cell cancers were determined to define cancer-related gene expression profiles. RNAs extracted from microdissected tissues were amplified by SMART technology and used as probes for hybridization of commercially available cDNA array filters comprising 1,176 cancer-related genes. Ninetytwo differentially expressed genes were identified by comparison of pooled cDNA from CIN3 vs. cervical cancer. Heterogeneity in expression of this subset of genes was then analyzed for each biopsy using an algorithm for self-organizing maps. For several gene clusters, the expression pattern for CIN3 differed significantly from that of cancer. Moreover, hierarchical clustering revealed significant differences in distribution of CIN and cancer. Several CIN cases were more strongly related to cancer, suggesting that gene expression profiling may be useful for subdividing pathologically indistinguishable precancers into different biologic entities. This approach also provides a basis for the identification of putative prognostic markers and for targeted molecular therapy.

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“…The anti-Cdc2 antiserum was provided by Dr N Watanabe (Watanabe et al, 1995). The polyclonal anti-cyclin D1 antiserum was kindly provided by Dr W Jiang (Poon et al, 1996).…”

Section: Antibodiesmentioning

confidence: 99%

Induction of growth arrest and cell death by overexpression of the cyclin-Cdk inhibitor p21 in hamster BHK21 cells

Sekiguchi¹,

Hunter²

1998

Oncogene

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p21 cip1/waf1/sdi1 is a universal cyclin-Cdk kinase inhibitor that has two functional domains; one binds and inhibits cyclin-Cdk activity and the other binds PCNA and thereby inhibits elongation by DNA polymerase. When transiently expressed in hamster BHK21 cells we found that human p21 was able to cause cell cycle arrest in G1 phase; this arrest was counteracted by coexpression of E2F-1 or SV40 large T antigen. To study the e ect of p21 overexpression in vivo, BHK21 cell clones inducibly expressing human p21 (Tet-p21) driven by the tetracycline (Tet)-repressible promoter were established. The maximum induced p21 levels in the absence of Tet were estimated to be ten times that of endogenous hamster p21. As p21 levels rose following removal of Tet, p21-associated histone H1 kinase activity was increased and concomitantly cell growth and DNA synthesis were reduced. Tet-p21 BHK21 cells became arrested in G1 phase and lost colony forming ability irreversibly 2 ± 4 days after removal of Tet. The induction of cyclin E-and cyclin A-associated kinase activities was diminished when G0-synchronized Tet-p21 BHK21 cells were serum stimulated in the absence of Tet. Increased binding of p21 to PCNA and cyclin D1-Cdk4 was detected in induced cells. Overexpression of p21 led to cell death in BHK21 cells at 39.58C within 4 days.

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Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle.

Cited by 403 publications

References 82 publications

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

Detection of cancer‐related gene expression profiles in severe cervical neoplasia

Induction of growth arrest and cell death by overexpression of the cyclin-Cdk inhibitor p21 in hamster BHK21 cells

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