Delayed early embryonic lethality following disruption of the murine cyclin A2 gene

Murphy, Martin J.; Stinnakre, Marie‐Georges; Sénamaud-Beaufort, Catherine; Winston, Nicola J.; Sweeney, Claire; Kubelka, Michal; Carrington, Mark; Bréchot, Christian; Sobczak-Thépot, Joëlle

doi:10.1038/ng0197-83

Cited by 247 publications

(189 citation statements)

References 18 publications

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“…which might be explained by complementation of cyclin A function by cyclin A1 during early embryonic development. 49 Since cyclin A1 mRNA is absent from mature peripheral blood leukocytes but expressed in a LP with a high CD34 + cell count from a healthy donor, we suggest that cyclin A1 might be necessary for proliferation and differentiation of early hematopoietic progenitor cells. Consequently, the leukemic counterparts of normal hematopoietic progenitors may express cyclin A1 because they are arrested at that early stage of differentiation.…”

Section: Discussionmentioning

confidence: 79%

Cyclin A1 is predominantly expressed in hematological malignancies with myeloid differentiation

et al. 1998

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Cyclin A is a cell cycle regulatory protein that functions in mitotic and S phase control in mammalian cells. However, in contrast to other G 1 phase regulatory proteins, such as cyclin D, retinoblastoma protein and p16 INK4A , cyclin A seems not to be commonly involved in tumorigenesis. Recently, a second human cyclin A -cyclin A1 -has been identified. In contrast to cyclin A which is expressed throughout embryonic development and in adult tissue, the expression of cyclin A1 has been reported to be restricted to embryonic and germ line cells. We have confirmed the absence of cyclin A1 mRNA from normal peripheral blood leukocytes of seven healthy donors by single step reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore, we have examined the expression of cyclin A1 mRNA in 173 peripheral blood samples of 162 patients with various hematological malignancies. Cyclin A1 mRNA was detectable in 11 of 11 patients with acute myeloid leukemia, three of three patients with acute biphenotypic leukemia, eight of eight patients with myelodysplastic syndrome, 59 of 69 patients with chronic myelogenous leukemia (CML) at diagnosis, 13 of 15 patients with CML in blastic transformation, 10 of 18 patients with chronic lymphocytic leukemia, two of nine patients with essential thrombocythemia, and only two of 10 patients with acute lymphoblastic leukemia (ALL) with both cyclin A1 RT-PCR positive ALL leukemias being undifferentiated relapses. In addition, cyclin A1 mRNA was found in one of six leukapheresis products, harvested from individuals without hematological disorders. Taken together, cyclin A1 is expressed in the majority of myeloid and undifferentiated hematological malignancies as well as in normal hematopoietic progenitor cells. We conclude that cyclin A1, a protein potentially involved in G 1 /S phase progression of immature cells, might be necessary for proliferation of early hematopoietic progenitor cells and their leukemic counterparts being blocked at that stage of differentiation.

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Section: Discussionmentioning

confidence: 79%

Cyclin A1 is predominantly expressed in hematological malignancies with myeloid differentiation

et al. 1998

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“…36 In contrast, cyclin A2 is present in proliferating somatic cells, and the cyclin A2 gene is embryonic lethal if disrupted. 37 Thus, synthesis of cyclin A2 and its binding to CDKs during cell cycle are widely characterized and can be considered essential in carcinogenesis and cancer prognostics, whereas the role of cyclin A1 remains less evident in solid tumors. 38 It is unknown whether the isoforms have any confounding effect in gastric cancer prognostics, but we consider it unlikely.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of cyclin A in gastric cancer

Mrena

Wiksten

Kokkola

et al. 2006

Intl Journal of Cancer

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High level of cyclin A promotes carcinogenesis, and overexpression of cyclin A has been associated with poor prognosis of cancer patients. We validated the prognostic role of cyclin A in gastric cancer and evaluated its correlation with expression of an mRNA stability factor HuR. From 342 consecutive histologically confirmed gastric cancer patients were obtained 325 representative tissue specimens for cyclin A and 316 for HuR immunohistochemistry. Specimens were stained by cyclin A and HuR specific monoclonal antibodies. Nuclear immunostaining detected in 5% of the tumor cells was considered the cut-off for cyclin A positivity. Positive HuR immunoreactivity was scored as nuclear or cytoplasmic. Associations between scores, clinicopathological factors and survival were calculated by the v 2 -test, Fisher's exact test, Kaplan-Meier test and Cox model. Cyclin A detected in the nuclei of cancer cells was positive in 55% (179 of 325) of the specimens; 40% (127 of 316) of the specimens had cytoplasmic and 88% (279 of 316) nuclear immunoreactivity of HuR. Cyclin A expression was an independent prognostic factor for poor survival. Cyclin A immunoreactivity was associated with old age, high stage, proximal location of the tumor, intestinal type, noncurative resection, advanced penetration depth and with nodal metastases but not distant metastases. Furthermore, cyclin A expression was associated with cytoplasmic HuR expression, whereas no association with nuclear HuR was evident. Cyclin A is an independent prognostic factor in gastric cancer, and one mechanism for its overexpression may depend on cytoplasmic localization of HuR. ' 2006 Wiley-Liss, Inc.Key words: cyclin A; HuR; gastric cancer; prognosis; survival Cyclin A belongs to the cyclin protein superfamily, and it can activate two different cyclin-dependent kinases, CDK1 and CDK2. The level of cyclin A accumulates progressively throughout the interphase and disappears rapidly at the end of mitosis. Currently, phosphorylated cyclin A-CDK complex is suggested to play an important role in the initiation of DNA replication in the S phase. The precise function of cyclin A in mitosis is unclear, but it may prevent other cyclins from degradation. Overexpression of cyclin A and dysregulation of CDK-cyclin complexes promote tumor cell growth, which can be facilitated by phosphorylation of oncoproteins and tumor suppressors. 1,2 In gastric cancer, cell-cycle regulators have been connected with poor prognosis. For example, overexpression of cyclin E, which also binds to CDK2 and controls the G1-S transition, has been associated with aggressive disease. 3,4 Furthermore, strongly positive cyclin E in the tumors of patients having surgery with intent to cure is a marker of poor prognosis, and concurrent expression of cyclin E and p53 is an independent prognostic factor. 5 However, there are also reports indicating that cyclin E expression does not correlate with clinicopathological parameters, 6 or is associated with good prognosis. 7 Overexpression of cyclin A correlates with po...

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“…Whereas maximal periodic cyclin E-Cdk2 activity is detected at G1/S, low levels of cyclin A-Cdk2 activity are first detected in late G1 phase, steadily increase as cells begin to replicate their DNA, and do not decline until cyclin A is degraded in early mitosis. Notably, while neither cyclin E1 nor E2 is essential for cell cycle progression during mouse development Parisi et al 2003; see below), cyclin A2 disruption results in early embryonic lethality (Murphy et al 1997). In S phase, cyclin A-Cdk2 is thought to phosphorylate substrates that start DNA replication from preassembled replication initiation complexes (Krude et al 1997;Hua and Newport 1998;Coverley et al 2002) and to be required for coordinating the end of S phase with activation of the mitotic Cdks (Mitra and Enders 2004).…”

Section: G1 Regulation In Mammalian Cellsmentioning

confidence: 99%

Living with or without cyclins and cyclin-dependent kinases

Sherr¹,

Roberts²

2004

Genes Dev.

977

882

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Entry into, progression through, and exit from the G1 phase of the mammalian cell cycle in response to extracellular mitogenic cues are presumed to be governed by cyclin-dependent kinases (Cdks) regulated by the D-type and E-type cyclins. Studies performed over more than a decade have supported the view that these holoenzymes are important, if not required, for these processes. However, recent experiments in which the genes encoding all three D-type cyclins, the two E-type cyclins, cyclin Ddependent Cdk4 and Cdk6, or cyclin E-dependent Cdk2 have been disrupted in the mouse germ line have revealed that much of fetal development occurs normally in their absence. Thus, none of these genes is strictly essential for cell cycle progression. To what extent is the prevailing dogma incorrect, and how can the recent findings be reconciled with past work?

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Delayed early embryonic lethality following disruption of the murine cyclin A2 gene

Cited by 247 publications

References 18 publications

Cyclin A1 is predominantly expressed in hematological malignancies with myeloid differentiation

Cyclin A1 is predominantly expressed in hematological malignancies with myeloid differentiation

Prognostic significance of cyclin A in gastric cancer

Living with or without cyclins and cyclin-dependent kinases

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