Disease relevance of CCNA2

• The human cyclin A gene was identified as the site of integration of hepatitis B virus in a hepatocarcinoma cell line; in addition, cyclin A is associated with the E2F transcription factor in a complex which is dissociated by the E1A oncogene product [1].
• We have produced human cyclin A in Escherichia coli and investigated how it generates H1 kistone kinase activity when added to cyclin-free extracts prepared from parthenogenetically activated Xenopus eggs [2].
• We have previously shown that the promoter complex HiNF-D, which interacts with cell cycle control elements in multiple histone genes, contains the key cell cycle factors cyclin A, CDC2, and a retinoblastoma (pRB) protein-related protein [3].
• In particular, well differentiated cells in squamous cell carcinoma stained positively for cyclin E; in contrast, cyclin A was expressed in the nonkeratinized proliferating areas of the tumor nests [4].
• Proliferative activity was assessed in serial sections by determining the expression of the cell cycle proteins Ki-67 and cyclin A. p27kip1 protein was significantly reduced in oral dysplasias and carcinomas compared with that in normal epithelial controls [5].

High impact information on CCNA2

• Y88 phosphorylation does not prevent p27 binding to cyclin A/Cdk2 [6].
• In postmitotic mutant cells, levels of Cyclin E and Cyclin A are elevated [7].
• p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase [8].
• Solution structure of the C-terminal core domain of human TFIIB: similarity to cyclin A and interaction with TATA-binding protein [9].
• Similarities between the TFIIBc and cyclin A folds indicate that elements of the eukaryotic cell cycle control apparatus evolved from more fundamental transcriptional control components, demonstrating a link between the transcription and cell cycle molecular machineries [9].

Chemical compound and disease context of CCNA2

• We investigated the temporal regulation of cyclin A- and B1-dependent kinases in human lymphoma cells treated with nitrogen mustard (HN2) and pentoxifylline, to determine whether the activity of these complexes correlated with cell cycle arrest induced by DNA damage [10].
• Tumor necrosis factor alpha inhibits cyclin A expression and retinoblastoma hyperphosphorylation triggered by insulin-like growth factor-I induction of new E2F-1 synthesis [11].
• Butyrolactone I inhibited phosphorylation of pRB catalyzed by cyclin A-cdk2 produced by baculovirus in vitro [12].
• Here we have expressed a full-length human cyclin A in Escherichia coli and purified the protein to homogeneity by virtue of an N-terminal histidine tag [13].
• Immunohistochemical expression of cyclins, cyclin-dependent kinases, tumor-suppressor gene products, Ki-67, and sex steroid receptors in endometrial carcinoma: positive staining for cyclin A as a poor prognostic indicator [14].

Biological context of CCNA2

• As p33cdk2 is bound to cyclin A and is targeted by the viral E1A protein, we suggest that the p33cdk2/cyclin A complex has a unique role in cell-cycle regulation of vertebrate cells [15].
• Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic up-regulation of cyclin A-associated cyclin-dependent kinase 2(cdk2) activity [16].
• Thus, cyclin E opens a 'window of opportunity' for replication complex assembly that is closed by cyclin A. The dual functions of cyclin A ensure that the assembly phase (G1) ends before DNA synthesis (S) begins, thereby preventing re-initiation until the next cell cycle [17].
• Plk1 depletion neither prevents APC phosphorylation nor cyclin A destruction in vivo [18].
• Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint [19].

Anatomical context of CCNA2

• However, recently, both cyclin A and cyclin E have been implicated as regulators of centrosome replication, and it is unclear when and where these cyclin-Cdks can interact with cytoplasmic substrates [20].
• Cyclin A2 regulates nuclear-envelope breakdown and the nuclear accumulation of cyclin b1 [21].
• We report here that reducing cyclin A expression by RNA interference (RNAi) in primary human fibroblasts inhibited activation of Cdc25B and Cdc25C and dephosphorylation of Cdk1 on tyrosine (tyr) 15 [22].
• Previous work has suggested that while cyclin B is capable of triggering cyclin destruction in Xenopus cell-free systems, cyclin A-associated kinase is not able to support this function [13].
• 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 [23].

Associations of CCNA2 with chemical compounds

• Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition [24].
• Cyclin A overexpression does not enhance transcriptional activation by an ER derivative bearing serine-to-alanine changes at residues 104, 106, and 118 [25].
• Pentoxifylline also reverted the activity of cyclin A- and B1-kinases in HN2-treated cells to approximately that observed in controls [10].
• A factor binding to the B-myb CHR was identified in fractionated HeLa nuclear extract and found to interact with the minor groove, as previously shown by in vivo footprinting for the cyclin A CHR [26].
• The ability of various cyclin D1 mutants to overcome the ICI 182780 mediated growth arrest corresponded with their ability to stimulate cyclin A- and E2F- promoter based reporter activities in the presence of ICI 182780 [27].

Physical interactions of CCNA2

• The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A [28].
• Finally, we show that multiprotein complex formation involving p45(SKP2)-CUL-1 and p19(SKP1) is governed, in part, by periodic, S phase-specific accumulation of the p45(SKP2) subunit and by the p45(SKP2)-bound cyclin A-CDK2 [29].
• Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex [30].
• Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase [31].
• The interaction of the retinoblastoma susceptibility gene product (Rb)-related p107 protein with the E2F transcription factor in S-phase cells facilitates the formation of a multicomponent complex also containing cyclin A and the p33cdk2 kinase [32].

Enzymatic interactions of CCNA2

• Thus, cdk2 and cyclin A proteins are components that assemble to yield a kinase complex that catalyzes the phosphorylation of histone H1 [33].

Regulatory relationships of CCNA2

• CDC2 or CDK2 monomers in lysates of infected cells could be activated by the addition of lysates containing cyclin A or B1 [34].
• Neither Cdk2T160A/cyclin A nor Cdk2T160E/cyclin A complexes were activated further by treatment with CAK [35].
• Granzyme B induces apoptosis and cyclin A-associated cyclin-dependent kinase activity in all stages of the cell cycle [36].
• Cyclin A1 but not cyclin A2 was upregulated in etoposide-treated tumor cells undergoing p53-dependent apoptosis and mitotic catastrophe [37].
• GAL4-E2F-1 deletion mutant studies indicated that cyclin A negatively regulates E2F function [38].
• Down-regulation of NFATc1 by its small interfering RNA inhibited PDGF-BB-induced cyclin A expression and DNA synthesis both in rat and human VSMC [39].

Other interactions of CCNA2

• These results thus define a cyclin A-cdk2 kinase complex that possesses sequence-specific DNA binding activity [40].
• A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F-cyclin A complex [40].
• Expression levels of cyclin E (P = 0.04) and cyclin A2 (P = 0.004) were significantly higher in the tumor samples than in normal controls [41].
• Cyclin A1, cyclin A2, and cyclin E2 expression levels did not have prognostic relevance for survival [41].
• Peptide competition studies have localized a cyclin A interaction site to a Lys381Lys382Leu383Met384Phe385 sequence within C-terminal negative regulatory domain of human p53 [28].
• SCAPER could play a role in distinguishing S phase- from M phase-specific functions of cyclin A/Cdk2 [42].

Analytical, diagnostic and therapeutic context of CCNA2

• Immunofluorescence studies have shown that both cyclins are nuclear and that a proportion of cyclin A is localized to sites of DNA replication [20].
• Immunoprecipitation also revealed higher levels of cyclin A and cyclin E associated with CDK2 in tumor tissues [4].
• Site-directed mutagenesis of Ser-154 abolished the phosphorylation by recombinant CDK2 in vitro and the majority of cyclin A phosphorylation in the cell [43].
• Moreover, expression of CA in tumors predicted a better response to chemotherapy [44].
• Cyclin A was also a powerful predictor of disease-free survival in T1-4/N0/M0 (P = 0.0027) tumours (P = 0.0007) [45].

References