The prognosis in spindle-cell sarcoma depends on the expression of cyclin-dependent kinase inhibitor p27Kip1 and cyclin E

ABSTRACT To understand how cellular differentiation is coupled to withdrawal from the cell cycle, we have focused on two negative regulators of the cell cycle, the MYC antagonist MAD1 and the cyclin-dependent kinase inhibitor p27KIP1. Generation of Mad1/p27KIP1 double-null mice revealed a number of synthetic effects between the null alleles of Mad1 and p27KIP1, including embryonic lethality, increased proliferation, and impaired differentiation of granulocyte precursors. Furthermore, with granulocyte cell lines derived from the Mad1/p27KIP1 double-null mice, we observed constitutive Myc expression and cyclin E-CDK2 kinase activity as well as impaired differentiation following treatment with an inducer of differentiation. By contrast, similar treatment of granulocytes from Mad1 or p27KIP1 single-null mice resulted in differentiation accompanied by downregulation of both Myc expression and cyclin E-CDK2 kinase activity. In the double-null granulocytic cells, addition of a CDK2 inhibitor in the presence of differentiation inducer was sufficient to restore differentiation and reduce Myc levels. We conclude that Mad1 and p27KIP1 operate, at least in part, by distinct mechanisms to downregulate CDK2 activity and Myc expression in order to promote cell cycle exit during differentiation.

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Estrogen-induced Activation of Cdk4 and Cdk2 during G1-S Phase Progression Is Accompanied by Increased Cyclin D1 Expression and Decreased Cyclin-dependent Kinase Inhibitor Association with Cyclin E-Cdk2

Journal of Biological Chemistry ◽

10.1074/jbc.272.16.10882 ◽

1997 ◽

Vol 272 (16) ◽

pp. 10882-10894 ◽

Cited By ~ 275

Author(s):

Owen W. J. Prall ◽

Boris Sarcevic ◽

Elizabeth A. Musgrove ◽

Colin K. W. Watts ◽

Robert L. Sutherland

Keyword(s):

Cyclin D1 ◽

Kinase Inhibitor ◽

Cyclin E ◽

S Phase ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

Phase Progression

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Expression of Cyclin E and Cyclin-Dependent Kinase Inhibitor, p27KIP1 in Uterine Endometrial Carcinoma: Relationship with p53 Status

International Journal of Surgical Pathology ◽

10.1177/106689699800600404 ◽

1998 ◽

Vol 6 (4) ◽

pp. 205-212 ◽

Cited By ~ 9

Author(s):

Hee Jeong Ahn ◽

Kae Won Kwon ◽

Yoon Jung Choi ◽

Nam Hoon Cho

Keyword(s):

Endometrial Carcinoma ◽

Kinase Inhibitor ◽

Cyclin E ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

P53 Status

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A Novel ALK Fusion Gene (NSF-ALK) Identified in a Patient With Recurrent Spindle Cell Sarcoma Respond to Crizotinib: A Case Report

10.21203/rs.3.rs-51702/v1 ◽

2020 ◽

Author(s):

Shuiling Jin ◽

Lanling Weng ◽

Qian Zhong ◽

Chi Cui ◽

Wenxue Tang ◽

...

Keyword(s):

Next Generation Sequencing ◽

Spindle Cell ◽

Kinase Inhibitor ◽

Fusion Gene ◽

Spindle Cell Sarcoma ◽

Next Generation ◽

Cell Sarcoma ◽

Anaplastic Lymphoma Kinase Inhibitor ◽

Anaplastic Lymphoma ◽

Generation Sequencing

Abstract Background: Spindle cell sarcoma (SCS) is a rare malignant tumor which relapses quickly and has poor prognosis.Case presentation: We report a case of SCS deriving from the left side of chestpossessed a novel unreported ALK fusion gene named NSF-ALK found by Next Generation Sequencing (NGS) technology. Despite receiving three surgical resections, local recurrence occurred rapidly and distant brain metastasis was eventually observed in this patient. The subsequent administration of crizotinib1, an oral anaplastic lymphoma kinase inhibitor, resulted in dramatic tumor shrinkage and the patient entered a remission period that has been ongoing for more than 10 months.Conclusions: In summary, this study is the first to describe a novel NSF-ALK fusion in spindle cell sarcoma which has promising efficacy by crizotinib treatment. More importantly, the case also shows that next generation sequencing provids more information of mutation to guide treatment in clinical decisions by presenting molecular changes.

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Expression of Cyclin E and the Cyclin-Dependent Kinase Inhibitor p27 in Malignant Lymphomas—Prognostic Implications

Blood ◽

10.1182/blood.v92.3.770 ◽

1998 ◽

Vol 92 (3) ◽

pp. 770-777 ◽

Cited By ~ 92

Author(s):

Martin Erlanson ◽

Cajsa Portin ◽

Barbro Linderholm ◽

Jack Lindh ◽

Göran Roos ◽

...

Keyword(s):

Cell Cycle ◽

Kinase Inhibitor ◽

Cyclin E ◽

Prognostic Significance ◽

S Phase ◽

Phase Fraction ◽

Serum Lactate Dehydrogenase ◽

Cyclin Dependent Kinase ◽

Malignant Lymphomas ◽

Cyclin Dependent Kinase Inhibitor

Abstract Cyclin E and the cyclin-dependent kinase inhibitor p27 are two important regulators of the G1-S transition modulating the activity of cyclin-dependent kinases. Aberrations in the cell cycle control are often observed in tumors and might even be mandatory in tumor development. To investigate the importance of cell-cycle defects in malignant lymphomas we have characterized the expression of cyclin E and p27 in 105 newly diagnosed lymphomas using immunohistochemistry. A significant, inverse correlation between p27 and cyclin E expression was observed (rs = −.24, P = .02) and both proteins correlated with the S-phase fraction (rs = −.35, P < .001 andrs = .45, P < .001, respectively). The inverse relationship between p27 expression and proliferation was abrogated in some lymphomas, suggesting that p27 downregulation can represent a genuine aberration. Survival analysis was performed in 105 patients with a median observation time of 86 months. Low p27 and high cyclin E expression were significantly associated with a poor prognosis (P = .0001 and .03, respectively). In a multivariate Cox analysis, p27 expression, stage, serum lactate dehydrogenase level, grade, and age were independent prognostic factors, in contrast to S-phase fraction and cyclin E expression. This is the first report showing that p27 expression in malignant lymphomas has independent prognostic significance, which necessitates future studies regarding its more precise biological role in lymphoid tumorogenesis. © 1998 by The American Society of Hematology.

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The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of differentiating neuroblastoma cells.

Molecular and Cellular Biology ◽

10.1128/mcb.16.4.1335 ◽

1996 ◽

Vol 16 (4) ◽

pp. 1335-1341 ◽

Cited By ~ 156

Author(s):

W Poluha ◽

D K Poluha ◽

B Chang ◽

N E Crosbie ◽

C M Schonhoff ◽

...

Keyword(s):

Cell Cycle ◽

Neuronal Differentiation ◽

Kinase Inhibitor ◽

Cyclin E ◽

Neuroblastoma Cells ◽

Protein Kinase Activity ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinases ◽

Cyclin Dependent Kinase Inhibitor ◽

Differentiated Cells

We are employing recent advances in the understanding of the cell cycle to study the inverse relationship between proliferation and neuronal differentiation. Nerve growth factor and aphidicolin, an inhibitor of DNA polymerases, synergistically induce neuronal differentiation of SH-SY5Y neuroblastoma cells and the expression of p21WAF1, an inhibitor of cyclin-dependent kinases. The differentiated cells continue to express p21WAF1, even after removal of aphidicolin from the culture medium. The p21WAF1 protein coimmunoprecipitates with cyclin E and inhibits cyclin E-associated protein kinase activity. Each of three antisense oligonucleotides complementary to p21WAF1 mRNA partially blocks expression of p21WAF1 and promotes programmed cell death. These data indicate that p21WAF1 expression is required for survival of these differentiating neuroblastoma cells. Thus, the problem of neuronal differentiation can now be understood in the context of negative regulators of the cell cycle.

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The Cyclin-dependent Kinase Inhibitor Dacapo Promotes Genomic Stability during Premeiotic S Phase

Molecular Biology of the Cell ◽

10.1091/mbc.e08-09-0916 ◽

2009 ◽

Vol 20 (7) ◽

pp. 1960-1969 ◽

Cited By ~ 11

Author(s):

Karine Narbonne-Reveau ◽

Mary Lilly

Keyword(s):

Dna Damage ◽

Kinase Inhibitor ◽

Cyclin E ◽

Genomic Stability ◽

S Phase ◽

Ovarian Cysts ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

Dna Replication Origins ◽

Meiotic Cycle

The proper execution of premeiotic S phase is essential to both the maintenance of genomic integrity and accurate chromosome segregation during the meiotic divisions. However, the regulation of premeiotic S phase remains poorly defined in metazoa. Here, we identify the p21Cip1/p27Kip1/p57Kip2-like cyclin-dependent kinase inhibitor (CKI) Dacapo (Dap) as a key regulator of premeiotic S phase and genomic stability during Drosophila oogenesis. In dap−/− females, ovarian cysts enter the meiotic cycle with high levels of Cyclin E/cyclin-dependent kinase (Cdk)2 activity and accumulate DNA damage during the premeiotic S phase. High Cyclin E/Cdk2 activity inhibits the accumulation of the replication-licensing factor Doubleparked/Cdt1 (Dup/Cdt1). Accordingly, we find that dap−/− ovarian cysts have low levels of Dup/Cdt1. Moreover, mutations in dup/cdt1 dominantly enhance the dap−/− DNA damage phenotype. Importantly, the DNA damage observed in dap−/− ovarian cysts is independent of the DNA double-strands breaks that initiate meiotic recombination. Together, our data suggest that the CKI Dap promotes the licensing of DNA replication origins for the premeiotic S phase by restricting Cdk activity in the early meiotic cycle. Finally, we report that dap−/− ovarian cysts frequently undergo an extramitotic division before meiotic entry, indicating that Dap influences the timing of the mitotic/meiotic transition.

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