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Query: UNIPROT:P06889 (Mol)
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We demonstrate here that the E2F1 induced by DNA damage can bind to and promote the apoptotic function of p53 via the cyclin A binding site of E2F1. This function of E2F1 does not require its DP-1 binding, DNA binding, or transcriptional activity and is independent of mdm2. All the cyclin A binding E2F family members can interact and cooperate with p53 to induce apoptosis. This suggests a novel role for E2F in regulating apoptosis in response to DNA damage. Cyclin A, but not cyclin E, prevents E2F1 from interacting and cooperating with p53 to induce apoptosis. However, in response to DNA damage, cyclin A levels decrease, with a concomitant increase in E2F1-p53 complex formation. These results suggest that the binding of E2F1 to p53 can specifically stimulate the apoptotic function of p53 in response to DNA damage.
Mol Cell Biol 2002 Jan
PMID:Novel function of the cyclin A binding site of E2F in regulating p53-induced apoptosis in response to DNA damage. 1173 24

p27(Kip1) is an important effector of G(1) arrest by transforming growth factor beta (TGF-beta). Investigations in a human mammary epithelial cell (HMEC) model, including cells that are sensitive (184(S)) and resistant (184A1L5(R)) to G(1) arrest by TGF-beta, revealed aberrant p27 regulation in the resistant cells. Cyclin E1-cyclin-dependent kinase 2 (cdk2) and cyclin A-cdk2 activities were increased, and p27-associated kinase activity was detected in 184A1L5(R) cells. p27 from 184A1L5(R) cells was localized to both nucleus and cytoplasm, showed an altered profile of phosphoisoforms, and had a reduced ability to bind and inhibit cyclin E1-cdk2 in vitro when compared to p27 from the sensitive 184(S) cells. In proliferating 184A1L5(R) cells, more p27 was associated with cyclin D1-cdk4 complexes than in 184(S). While TGF-beta inhibited the formation of cyclin D1-cdk4-p27 complexes in 184(S) cells, it did not inhibit the assembly of cyclin D1-cdk4-p27 complexes in the resistant 184A1L5(R) cells. p27 phosphorylation changed during cell cycle progression, with cyclin E1-bound p27 in G(0) showing a different phosphorylation pattern from that of cyclin D1-bound p27 in mid-G(1). These data suggest a model in which TGF-beta modulates p27 phosphorylation from its cyclin D1-bound assembly phosphoform to an alternate form that binds tightly to inhibit cyclin E1-cdk2. Altered phosphorylation of p27 in the resistant 184A1L5(R) cells may favor the binding of p27 to cyclin D1-cdk4 and prevent its accumulation in cyclin E1-cdk2 in response to TGF-beta.
Mol Cell Biol 2002 May
PMID:Altered p27(Kip1) phosphorylation, localization, and function in human epithelial cells resistant to transforming growth factor beta-mediated G(1) arrest. 1194 Jun 57

The function of cyclin G, a commonly induced p53 target, has remained elusive. We show that cyclin G forms a quaternary complex in vivo and in vitro with enzymatically active phosphatase 2A (PP2A) holoenzymes containing B' subunits. Interestingly, cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells. Cyclin G expression also results in reduced phosphorylation of human Hdm2 at S166. Thus, our data suggest that cyclin G recruits PP2A in order to modulate the phosphorylation of Mdm2 and thereby to regulate both Mdm2 and p53.
Mol Cell 2002 Apr
PMID:Cyclin G recruits PP2A to dephosphorylate Mdm2. 1198 68

cdk4 mRNA and protein are constitutively expressed in sea urchin eggs and throughout embryonic development. In contrast, cyclin D mRNA is barely detectable in eggs and early embryos, when the cell cycles consist of alternating S and M phases. Cyclin D mRNA increases dramatically in embryos at the early blastula stage and remains at a constant level throughout embryogenesis. An increase in cdk4 kinase activity occurs concomitantly with the increase in cyclin D mRNA. Ectopic expression of cyclin D mRNA in eggs arrests development before the 16-cell stage and causes eventual embryonic death, suggesting that activation of cyclin D/cdk4 in cleavage cell cycles is lethal to the embryo. In contrast, blocking cyclin D or cdk4 expression with morpholino antisense oligonucleotides results in normal development of early gastrula-stage embryos but abnormal, asymmetric larvae. These results suggest that in sea urchins, cyclin D and cdk4 are required for normal development and perhaps the patterning of the developing embryo, but may not be directly involved in regulating entry into the cell cycle.
Mol Cell Biol 2002 Jul
PMID:Cyclin D and cdk4 are required for normal development beyond the blastula stage in sea urchin embryos. 1205 92

Cyclin-dependent kinases (CDKs) are important for both mitotic and meiotic cell cycles. In fission yeast, the major CDK, Cdc2p is involved in premeiotic DNA replication and in meiosis II. One of its partners, the mitotic cyclin Cdc13p is known to be required for meiosis, whereas there are no studies on the G1/S cyclin Cig2p. In this article, we have studied the regulation of the Cdc2p/Cdc13p and Cdc2p/Cig2p complexes during synchronous meiosis. We observed that Cdc2p/Cig2p kinase is activated in an unexpected biphasic manner, first at onset of premeiotic S phase and again during meiotic nuclear divisions. The role of Cig2p during meiosis was investigated using cig2-deleted strains that exhibit delays in onset of both S phase and meiotic divisions as well as an inefficient completion of MII. Furthermore, analysis of cig2 transcripts revealed a meiosis-specific regulation of cig2 expression during MI/MII dependent upon the Mei4p transcription factor leading to a different transcription start site at this stage of meiosis.
Mol Biol Cell 2002 Jun
PMID:The G1/S cyclin Cig2p during meiosis in fission yeast. 1205 71

Cyclin-dependent kinases (Cdks) are key regulators of the cell division cycle. Pho85 is a multifunctional Cdk in budding yeast involved in aspects of metabolism, the cell cycle, cell polarity, and gene expression. Consistent with a broad spectrum of functions, Pho85 associates with a family of 10 cyclins and deletion of PHO85 causes a pleiotropic phenotype. Discovering the physiological substrates of protein kinases is a major challenge, and we have pursued a number of genomics approaches to reveal the processes regulated by Pho85 and to understand the root cause of reduced cellular fitness in pho85Delta mutant strains. We used a functional-genomics approach called synthetic genetic array (SGA) analysis to systematically identify strain backgrounds in which PHO85 is required for viability. In parallel, we used DNA microarrays to examine the genome-wide transcriptional consequences of deleting PHO85 or members of the Pho85 cyclin family. Using this pairwise approach coupled with phenotypic tests, we uncovered clear roles for Pho85 in cell integrity and the response to adverse growth conditions. Importantly, our combined approach allowed us to ascribe new aspects of the complex pho85 phenotype to particular cyclins; our data highlight a cell integrity function for the Pcl1,2 subgroup of Pho85 Cdks that is independent of a role for the Pho80-Pho85 kinase in the response to stress. Using a modification of the SGA technique to screen for suppressors of pho85Delta strain growth defects, we found that deletion of putative vacuole protein gene VTC4 suppressed the sensitivity of the pho85Delta strain to elevated CaCl(2) and many other stress conditions. Expression of VTC4 is regulated by Pho4, a transcription factor that is inhibited by the Pho80-Pho85 kinase. Genetic tests and electron microscopy experiments suggest that VTC4 is a key target of Pho4 and that Pho80-Pho85-mediated regulation of VTC4 expression is required for proper vacuole function and for yeast cell survival under a variety of suboptimal conditions. The integration of multiple genomics approaches is likely to be a generally useful strategy for extracting functional information from pleiotropic mutant phenotypes.
Mol Cell Biol 2002 Jul
PMID:Dissection of a complex phenotype by functional genomics reveals roles for the yeast cyclin-dependent protein kinase Pho85 in stress adaptation and cell integrity. 1207 37

In higher eukaryotes, the proliferating cell nuclear antigen (PCNA) can be found associated to Cyclin D and Cdk4/6, the kinase complex responsible for cell cycle commitment in response to growth and mitogenic signals. During maize germination, PCNA can be found in protein complexes between 131 and 163 kDa. The sizes of PCNA protein complexes seem to change during germination, so that by the time the S phase starts, a complex of 100 kDa (likely the homotrimeric ring) is the predominant one. PCNA complexes during early germination contain (any of) two PSTAIRE-containing protein kinases of 32 and 36 kDa that readily phosphorylate both histone H1 and maize retinoblastoma-related (RBR) proteins. Kinase activity in PCNA complexes is markedly inhibited by roscovitine and olomoucine, two known Cdk inhibitors. The protein p13(Suc1) only pulls down the 36 kDa PSTAIRE protein. Kinase activity in PCNA immunoprecipitates is maximal during early germination, before the onset of the S-phase, whereas kinase activity associated to pl3(Suc1) reaches a peak later, after the onset of the S-phase. We discuss the physiological repercussions of these findings.
Plant Mol Biol 2002 Sep
PMID:PCNA protein associates to Cdk-A type protein kinases in germinating maize. 1217 10

Cyclin-dependent kinases (Cdks) were originally identified as regulators of eukaryotic cell cycle progression, but several Cdks were subsequently shown to perform important roles as transcriptional regulators. While the mechanisms regulating the Cdks involved in cell cycle progression are well documented, much less is known regarding how the Cdks that are involved in transcription are regulated. In Saccharomyces cerevisiae, Bur1 and Bur2 comprise a Cdk complex that is involved in transcriptional regulation, presumably mediated by its phosphorylation of the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II. To investigate the regulation of Bur1 in vivo, we searched for high-copy-number suppressors of a bur1 temperature-sensitive mutation, identifying a single gene, CAK1. Cak1 is known to activate two other Cdks in yeast by phosphorylating a threonine within their conserved T-loop domains. Bur1 also has the conserved threonine within its T loop and is therefore a potential direct target of Cak1. Additional tests establish a direct functional interaction between Cak1 and the Bur1-Bur2 Cdk complex: Bur1 is phosphorylated in vivo, both the conserved Bur1 T-loop threonine and Cak1 are required for phosphorylation and Bur1 function in vivo, and recombinant Cak1 stimulates CTD kinase activity of the purified Bur1-Bur2 complex in vitro. Thus, both genetic and biochemical evidence demonstrate that Cak1 is a physiological regulator of the Bur1 kinase.
Mol Cell Biol 2002 Oct
PMID:Activation of the Bur1-Bur2 cyclin-dependent kinase complex by Cak1. 1221 32

Cyclin A is particularly interesting among the cyclin family because it can activate two different cyclin-dependent kinases (CDKs) and functions in both S phase and mitosis. An embryonic form of cyclin A that is only essential for spermatogenesis is also present in some organisms. In S phase, phosphorylation of components of the DNA replication machinery such as CDC6 by cyclin A-CDK is believed to be important for initiation of DNA replication and to restrict the initiation to only once per cell cycle. In mitosis, the precise role of cyclin A is still obscure, but it may contribute to the control of cyclin B stability. Cyclin A starts to accumulate during S phase and is abruptly destroyed before metaphase. The synthesis of cyclin A is mainly controlled at the transcription level, involving E2F and other transcription factors. Removal of cyclin A is carried out by ubiquitin-mediated proteolysis, but whether the same anaphase-promoting complex/cyclosome targeting subunits are used as for cyclin B is debatable. Consistent with its role as a key cell cycle regulator, expression of cyclin A is found to be elevated in a variety of tumors.
Cell Mol Life Sci 2002 Aug
PMID:Cyclin A in cell cycle control and cancer. 1236 35

Cyclin mRNAs are unstable in the adult cell cycle yet are stable during the first 12 cell divisions in Xenopus laevis. We recently reported that cyclin A1 and B2 maternal mRNAs are deadenylated upon completion of the 12th division (Audic et al. [2001] Mol. Cell Biol. 21:1662-1671). Deadenylation is mediated by the 3' untranslated region (UTR) of the mRNA and precedes the terminal disappearance of the cyclin proteins, with both processes requiring zygotic transcription. The purpose of the current study was (1) to ask whether deadenylation leads to translational repression and/or destabilization of endogenous cyclin A1 and B2 mRNAs, and (2) to further characterize the regulatory sequences required. We show that zygote-driven deadenylation leads to translational repression and mRNA destabilization. A 99-nucleotide region of the 3'UTR of the cyclin A1 mRNA mediates both deadenylation and destabilization. Surprisingly, two AU-rich consensus elements within this region are dispensable for this activity. These results suggest that zygote-dependent deadenylation, translational repression, and mRNA destabilization by means of novel 3'UTR elements contribute to the disappearance of maternal cyclins. They also suggest that translational control of cyclins may play a role in the transition to the adult cell cycle. These data concur with previous studies in Drosophila showing that zygote-mediated degradation of maternal cdc25 mRNA may be a general mechanism whereby transition to the adult cell cycle proceeds.
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PMID:Zygotic control of maternal cyclin A1 translation and mRNA stability. 1245 27


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