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

Abundance and activity of p53 are predominantly regulated posttranslationally. Structural disturbance in transcribed genes induced by radiation, e.g. DNA damage, or by transcriptional inhibitors cause p53 protein stabilization by a yet unknown mechanism. Using stable and transient transfections for the analysis of p53 mutant proteins, we have ruled out a role in stabilization by UV, gamma irradiation or actinomycin C for the following putative phosphorylation sites in the p53 protein: serines 6, 9, 15, 33, 315 and 392, and threonine 18. By double mutation combinations of phosphorylations were also ruled out; 6,9; 15,18; 15,37. These mutations eliminate modifications by casein kinases I and II, DNA-PK, ATM, CDK and JNK. Also the 30 carboxyterminal amino acids are not required for induced p53 stabilization. Thus neither phosphorylations of individual amino acids nor interactions of the carboxyterminus of p53 with cellular macromolecules appear to play a role in the stabilization process. The only single prerequisite for induced stabilization of p53 is its prior destabilization by Mdm2. However, the level of active Mdm2 must be controlled carefully: overexpression of Mdm2 inhibits UV induced p53 stabilization.
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PMID:DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation. 1020 33

Genetic lesions that disable key regulators of G1 phase progression in mammalian cells are present in most human cancers. Mitogen-dependent, cyclin D-dependent kinases (cdk4 and cdk6) phosphorylate the retinoblastoma (Rb) tumor suppressor protein, helping to cancel its growth-inhibitory effects and enabling E2F transcription factors to activate genes required for entry into the DNA synthetic phase (S) of the cell division cycle. Among the E2F-responsive genes are cyclins E and A, which combine with and activate cdk2 to facilitate S phase entry and progression. Accumulation of cyclin D-dependent kinases during G1 phase sequesters cdk2 inhibitors of the Cip/Kip family, complementing the effects of the E2F transcriptional program by facilitating cyclin E-cdk2 activation at the G1-S transition. Disruption of "the Rb pathway" results from direct mutational inactivation of Rb function, by overexpression of cyclin D-dependent kinases, or through loss of p16(INK4a), an inhibitor of the cyclin D-dependent kinases. Reduction in levels of p27(Kip1) and increased expression of cyclin E also occur and carry a poor prognostic significance in many common forms of cancer. The ARF tumor suppressor, encoded by an alternative reading frame of the INK4a-ARF locus, senses "mitogenic current" flowing through the Rb pathway and is induced by abnormal growth promoting signals. By antagonizing Mdm2, a negative regulator of the p53 tumor suppressor, ARF triggers a p53-dependent transcriptional response that diverts incipient cancer cells to undergo growth arrest or apoptosis. Although ARF is not directly activated by signals that damage DNA, its loss not only dampens the p53 response to abnormal mitogenic signals but also renders tumor cells resistant to treatment by cytotoxic drugs and irradiation. Lesions in the p16--cyclin D-CDK4--Rb and ARF--Mdm2--p53 pathways occur so frequently in cancer, regardless of patient age or tumor type, that they appear to be part of the life history of most, if not all, cancer cells.
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PMID:The Pezcoller lecture: cancer cell cycles revisited. 1091 34

Unraveling the mechanisms underlying cellular senescence will contribute to the understanding of processes involved in aging and cancer. We sought to determine whether expression of cellular factors in senescent WI-38 human fibroblasts was sufficient to induce nuclear DNA synthesis. Expression by recombinant adenovirus of E2F1, E2F2, E2F3, cyclin E/cdk2, and Mdm2 individually resulted in DNA synthesis in 10-30% of cells. However, combination of Mdm2 with E2F or cyclin E/cdk2 resulted in 50 to 75% of cells synthesizing DNA. DNA synthesis occurred approximately 30 h following infection. We conclude that expression of normal cellular factors is sufficient to induce DNA synthesis in senescent normal human fibroblasts.
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PMID:Reconstitution of dna synthetic capacity in senescent normal human fibroblasts by expressing cellular factors E2F and Mdm2. 1164 Aug 90

ik3-2 is a close relative to ik3-1/Cables, an associator with cdk3 and cdk5. ik3-1/Cables has been identified to be a candidate tumor suppressor for colon and head/neck cancers. In agreement, it has been pointed out that ik3-1/Cables is a regulator for both p53- and p73-induced apoptosis [J. Biol. Chem. 277 (2002) 2951] although ectopic expression of ik3-1/Cables does not induce apoptosis. Here we show that adenovirus-mediated overexpression of ik3-2 results in apoptosis of p53-intact U2OS cells. ik3-2 binds to p53 in vivo and ectopic coexpression of ik3-2 enhances apoptosis induced by adenovirus-mediated expression of p53. Furthermore, ectopic expression of ik3-2 results in apoptosis of primary p53/Mdm2- and p53/ARF-null mouse embryo fibroblasts, indicating that ik3-2-induced apoptosis is partially p53-independent. Both the highly conserved C-terminal cyclin box-homologous domain (ik3-2-C) and the N-terminal region consisting of 70 amino acids (ik3-2-N) are responsible for ik3-2-mediated enhancement of p53-induced apoptosis. In contrast, ik3-2-induced p53-independent apoptosis is mediated through ik3-2-N. We thus identified ik3-2 as a proapoptotic factor involved in both p53-mediated and p53-independent apoptotic pathways.
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PMID:ik3-2, a relative to ik3-1/Cables, is involved in both p53-mediated and p53-independent apoptotic pathways. 1463 68

Imatinib metylase is the first choice treatment for BCR/ABL positive chronic myelogenous leukemia (CML). However, as some CML patients develop resistance to imatinib therapy, there is a significant interest in development of alternative treatment strategies, such as identifying targets other than BCR/ABL that may participate in CML. Previously, we demonstrated strong PCNA up-regulation in CML patients. To further study its role in CML pathogenesis, we performed silencing of PCNA expression followed by array experiments. PCNA inhibition led to down-regulation of CDK1, CDK4, PLK1, ERK3, JNK1, STAT5, and several inhibitors of apoptosis (DAXX, Mdm2, survivin). The following genes were up-regulated: CDK inhibitors p21 and p19-INK4D, pro-apoptotic FAST kinase, fibronectin, etc. However, as PCNA affects cell growth in naturally proliferating cells as well as in cancerous cells, it seems to act a secondary role relating to proliferation activity of leukemic cells.
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PMID:Expression analysis of PCNA gene in chronic myelogenous leukemia--combined application of siRNA silencing and expression arrays. 1707 Sep 5

In the present work, we have reviewed data showing that triiodothyronine and its nuclear receptors modify expression of different genes/proteins involved in cell cycle control beginning from growth factors (such as EGF and TGF-beta), to cell surface receptors (EGFR), as well as proteins acting at the cell membrane (Ras), various transcription factors (c-Fos, c-Myc, E2F1), cyclins, Cip/Kip family of cdk2 inhibitors, and p53 inhibitor Mdm2 (Table 1). We have shown how TRs are also able to modify the fate of a cell, thanks to their ability to form complexes with other transcription factors such as p53 - a key regulator of apoptosis and proliferation. Available data show that the function of thyroid hormones and of their receptors on cell proliferation is not homogenous. In fact, it strongly depends on the cell type, its developmental state (progenitor or differentiated), its patho-physiological state (normal or tumor cell), and the so-called 'cellular context'. Therefore, it is not possible to uniformly recommend T3 treatment or T3 depletion to stop or initiate proliferation of all cell types. Instead, a very individual and careful action should be considered.
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PMID:Thyroid hormones and their receptors in the regulation of cell proliferation. 1711 80

In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ERalpha) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7(Dnp53)) maintained nuclear ERalpha expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7(DNp53) cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERalpha expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7(DNp53) cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.
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PMID:Impaired p53 function leads to centrosome amplification, acquired ERalpha phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts. 1826 35

Senescence and apoptosis programs governed by the Rb and p53 signaling networks can counter tissue stem cell self-renewal. A master regulator of Rb and p53 is the INK4-ARF (CDKN2A/B) locus that encodes two CDK inhibitors, p16(INK4A) and p15(INK4B), that maintain Rb in its active, hypophosphorylated form, and p14(ARF) (p19(Arf) in mice), that inhibits Mdm2 and activates p53. The INK4-ARF genes are epigenetically silenced in hematopoietic stem cells but become poised to respond to oncogenic stress as blood cells differentiate. Inactivation of INK4-ARF endows differentiated cells with an inappropriate self-renewal capacity, a defining feature of cancer cells. In BCR-ABL-induced (Philadelphia chromosome-positive [Ph(+)]) leukemias, INK4-ARF deletions frequently occur in clinically aggressive acute lymphoblastic leukemias (Ph(+) ALLs) but are not seen in more indolent Ph(+) chronic myelogenous leukemia (CML) or in CML myeloid blast crisis. Mouse modeling of Ph(+) ALL reveals that Arf inactivation attenuates responsiveness to targeted BCR-ABL kinase inhibitors, enhances the maintenance of leukemia-initiating cells within the hematopoietic microenvironment, and facilitates the emergence of malignant clones that harbor drug-resistant BCR-ABL kinase mutations. Thus, although BCR-ABL mutations typify drug resistance in both CML and Ph(+) ALL, loss of INK4-ARF in Ph(+) ALL enhances disease aggressiveness and undermines the salutary effects of targeted therapy.
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PMID:The INK4-ARF (CDKN2A/B) locus in hematopoiesis and BCR-ABL-induced leukemias. 1902 87

Cellular levels of products from both oncogenes and tumor suppressor genes in normal cells need to be critically regulated to avoid malignant transformation. These products are often controlled by the ubiquitin proteasome pathway, the specific degradation mechanism in the cell. E3 ubiquitin ligases polyubiquitylate their specific substrates by collaborating with E1 and E2, and then the modified substrates are degraded in the proteasome. Mdm2 targets p53 and retinoblastoma protein, two major tumor suppressor gene products, for ubiquitin-dependent degradation. SCF(Skp2) targets other tumor suppressor gene products and CDK inhibitors such as p130, Tob1, p27(Kip1), p57(Kip2), and p21(Cip1). Therefore, both E3 ligases act like oncogene products. In contrast, degradation of several oncogene products, such as Cyclin E, Notch, c-Myc, c-Jun, and c-Myb, are mediated by SCF(Fbw7). Fbw7 is often deleted or mutated in human cancers and acts like a tumor suppressor. As well as growth factor receptors and signal transduction regulators, DNA repair-related proteins are also regulated via the ubiquitin-proteasome pathway mediated by their specific E3 ligases. The stabilization of oncogene products and enhanced degradation of tumor suppressor gene products or DNA repair proteins might be associated with carcinogenesis and malignant progression, due to defects or the abnormal expression of their E3 ligases.
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PMID:Ubiquitin-mediated control of oncogene and tumor suppressor gene products. 1945 46

In this paper, cell cycle in higher eukaryotes and their molecular networks signals both in G1/S and G2/M transitions are replicated in silico. Biochemical kinetics, converted into a set of differential equations, and system control theory are employed to design multi-nested digital layers to simulate protein-to-protein activation and inhibition for cell cycle dynamics in the presence of damaged genomes. Sequencing and controlling the digital process of four micro-scale species networks (p53/Mdm2/DNA damage, p21mRNA/cyclin-CDK complex, CDK/CDC25/weel/SKP2/APC/CKI and apoptosis target genes system) not only allows the comprehension of the mechanisms of these molecule interactions but paves the way for unraveling the participants and their by-products, until now quite unclear, which have the task of carrying out (or not) cell death. Whatever the running simulations (e.g., different species signals, mutant cells and different DNA damage levels), the results of the proposed cell digital multi-layers give reason to believe in the existence of a universal apoptotic mechanism. As a consequence, we identified and selected cell check points, sizers, timers and specific target genes dynamic both for influencing mitotic process and avoiding cancer proliferation as much as for leading the cancer cell(s) to collapse into a steady stable apoptosis phase.
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PMID:Cancer cell(s) cycle sequencing reveals universal mechanisms of apoptosis. 2114 76


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