Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytodifferentiation agent hexamethylene bisacetamide (HMBA) is an inducer of differentiation of a variety of transformed cells, including the murine erythroleukemia (MEL) cell line. Induction of differentiation of MEL cells is a multistep process resulting in cessation of cell division and phenotypic maturation (including hemoglobin production). To investigate HMBA-induced MEL cell differentiation, we have analyzed the regulation of the E2F transcription factor. E2F regulates the transcription of several genes whose products are involved in both cell cycle regulation and differentiation. In nuclear extracts from uninduced MEL cells, three complexes were detected using gel mobility assays with the E2F/E2 oligonucleotide. The complex with the fastest mobility is the free form of E2F binding to DNA, and the more slowly migrating complexes contain E2F, p107, and cdk2. By 8 h of HMBA induction and for the remainder of the differentiation process, the free E2F complex is not detected, and only complexes of slower mobility, which contain p107 and cdk2, are found. The level of p107 protein increases during induction of differentiation; there is no change in the level of cdk2 protein and E2F-4 and DP-1 proteins during the first 4 days. The level of E2F-1 mRNA does not change, but a new form of E2F is detected during induction of differentiation. Thus, HMBA causes a selective loss in the free E2F DNA-binding complex, an increase in p107 protein, and an increase in a form of E2F protein during MEL cell differentiation.
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PMID:Changes in E2F DNA-binding activity during induced erythroid differentiation. 878 31

In addition to its inhibitory activity against viral DNA polymerases and reverse transcriptase, the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) also markedly inhibits the replicative cellular DNA polymerases alpha, delta, and epsilon. We have previously shown that PMEA is a strong inducer of differentiation in several in vitro tumor cell models and has marked antitumor potential in vivo. To elucidate the molecular mechanism of the differentiation-inducing activity of PMEA, we have now investigated the effects of the drug on cell proliferation and differentiation, cell cycle regulation, and oncogene expression in the human erythroleukemia K562 cell line. Terminal, irreversible erythroid differentiation of PMEA-treated K562 cells was evidenced by hemoglobin production, increased expression of glycophorin A on the K562 cell membrane, and induction of acetylcholinesterase activity. After exposure to PMEA, K562 cell cultures displayed a marked retardation of S-phase progression, leading to a severe perturbation of the normal cell cycle distribution pattern. Whereas no substantial changes in c-myc mRNA levels and p21, PCNA, cdc2, and CDK2 protein levels were noted in PMEA-treated K562 cells, there was a marked accumulation of cyclin A and, most strikingly, cyclins E and B1. A similar picture of cell cycle deregulation was also observed in PMEA-exposed human myeloid THP-1 cells. However, in contrast to the strong differentiation-inducing activity of PMEA in K562 cells, the drug completely failed to induce monocytic maturation of human myeloid THP-1 cells. On the contrary, THP-1 cells underwent apoptotic cell death in the presence of PMEA, as demonstrated by prelytic, intracellular DNA fragmentation and the binding of annexin V to the cell surface. We hypothesize that, depending on the nature of the tumor cell line, PMEA triggers a process of either differentiation or apoptosis by the uncoupling of normally integrated cell cycle processes through inhibition of DNA replication during the S phase.
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PMID:9-(2-Phosphonylmethoxyethyl)adenine induces tumor cell differentiation or cell death by blocking cell cycle progression through the S phase. 1039 5

O(2)-(2,4-dinitro-5-{[2-(12-en-28-b-d-galactopyranosyl-oleanolate-3-yl)-oxy-2-oxoethyl]amino}phenyl)1-(N-hydroxyethylmethylamino)diazen-1-ium-1,2-diolate (NOAD), a novel NO-releasing derivative of oleanolic acid (OA), is an active cytotoxic component. In this study, NOAD induced a rise in intracellular NO levels and showed cytotoxic effects which were prevented by hemoglobin (NO scavenger). Meanwhile, NOAD induced G2/M phase cell cycle arrest in a concentration-dependent manner. Analysis of the cell cycle regulatory proteins demonstrated that NOAD did not change the steady-state levels of cyclin A, cyclin B, cyclin E, Cdk2 and Cdk4, but decreased the protein levels of Cdk1 and Cdc25C. Meanwhile, the levels of phosphorylation of Cdc25C and Cdk1 were significantly increased by NOAD in a concentration-dependent manner. Moreover, NOAD modulated the phosphorylation of protein kinases Chk2. During the G2/M arrest, cyclin-dependent kinase inhibitors (CDKIs), p21(WAF1/CIP1) and p27(kip1) were increased in a concentration-dependent manner. In addition, NOAD also caused a marked increase in the apoptotic cells, as characterized by fragmented nuclei, sub G1 formation, the level of 8-OHDG increase and poly (ADP-ribose) polymerase (PARP) cleavage, which was associated with activation of caspase-3, caspase-8 and caspase-9. Up-regulation of Bax and down-regulation of Bcl-2 were also observed in Bel-7402 cells treated with NOAD. These data suggest that NOAD produces anti-tumor effect via induction of G2/M cell cycle arrest and apoptosis.
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PMID:NOAD, a novel nitric oxide donor, induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma Bel-7402 cells. 2600 17

B cell CLL/lymphoma 11A (BCL11A) is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. In the hematopoietic system, BCL11A is required for B lymphopoiesis, yet its role in other hematopoietic cells, especially hematopoietic stem cells (HSCs) remains elusive. The extensive expression of BCL11A in hematopoiesis implicates context-dependent roles, highlighting the importance of fully characterizing its function as part of ongoing efforts for stem cell therapy and regenerative medicine. Here, we demonstrate that BCL11A is indispensable for normal HSC function. Bcl11a deficiency results in HSC defects, typically observed in the aging hematopoietic system. We find that downregulation of cyclin-dependent kinase 6 (Cdk6), and the ensuing cell-cycle delay, correlate with HSC dysfunction. Our studies define a mechanism for BCL11A in regulation of HSC function and have important implications for the design of therapeutic approaches to targeting BCL11A.
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PMID:Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype. 2765 84