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 CDKN2 gene, encoding the cyclin-dependent kinase-4 inhibitor p16, is a putative tumour-suppressor gene because it is frequently altered in many malignant tumours. We analysed the CDKN2 gene in 44 cases of adult T-cell leukaemia (ATL) by Southern blot analysis, polymerase chain reaction-mediated single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. Southern blot analysis detected a homozygous deletion of the CDKN2 gene in 5/44 patients (11.4%). Mutational analysis by the PCR-SSCP method and direct sequencing showed one nonsense mutation at codon 72 (nucleotide 232), and two missense mutations at codon 43 (nucleotide 146) and codon 97 (nucleotide 309, 3/44, 6.8%). Therefore we found changes in the CDKN2 gene, including point mutations, in 18.2% of the patients with ATL. Interestingly, most of these patients had acute type ATL. Our results suggest that the CDKN2 gene is inactivated not only by homozygous deletion but also by point mutation, and these alterations contribute to the aggressiveness of ATL.
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PMID:The CDKN2 gene alterations in various types of adult T-cell leukaemia. 882 90

We investigated the in vivo expression of cyclin B1 and Cdc2 (key molecules for G2-M transition during the cell cycle) in nonmalignant and cancerous human breast lesions using immunohistochemistry and quantitative proliferative index (PI) analysis. Breast epithelial cells co-expressed cyclin B1 and Cdc2 in their cytoplasm in the G2 phase and in their nuclei in the M phase. Cyclin B1, but not Cdc2, immunostaining rapidly disappeared from the nuclei during the mitotic metaphase to anaphase transition. Static image analysis revealed the mean proliferative index for cyclin B1/cdc2 for each type of lesion to be as follows: normal glands (n = 20), 2.0/2.5%; benign lesions, including typical ductal hyperplasia (n = 76), 2.5/5.8%; atypical ductal hyperplasia (n = 21), 3.0/6.6%; carcinomas in situ (n = 70), 7.4/14.0%; and invasive carcinomas (n = 58), 10.0/22.9%. Proliferative index data for atypical hyperplasia were virtually identical to those for benign lesions and were significantly lower than those for breast cancer, suggesting that expression levels of cyclin B1 and Cdc2 may be used to distinguish premalignant human breast lesions from advanced disease. Furthermore, the proliferative index for cyclin B1 for comedo-type ductal carcinomas in situ agreed with that for invasive ductal carcinomas (mean, 10.1% versus 9.5%), apparently explaining the clinicopathological aggressiveness of this tumor at the molecular level.
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PMID:Expression of the G2-M checkpoint regulators cyclin B1 and cdc2 in nonmalignant and malignant human breast lesions: immunocytochemical and quantitative image analyses. 900 17

Human melanoma cell lines derived from early stage primary tumors are particularly sensitive to growth arrest induced by interleukin-6 (IL-6). This response is lost in cell lines derived from advanced lesions, a phenomenon which may contribute to tumor aggressiveness. We sought to determine whether resistance to growth inhibition by IL-6 can be explained by oncogenic alterations in cell cycle regulators or relevant components of intracellular signaling. Our results show that IL-6 treatment of early stage melanoma cell lines caused G1 arrest, which could not be explained by changes in levels of G1 cyclins (D1, E), cdks (cdk4, cdk2) or by loss of cyclin/cdk complex formation. Instead, IL-6 caused a marked induction of the cdk inhibitor p21WAF1/CIP1 in three different IL-6 sensitive cell lines, two of which also showed a marked accumulation of the cdk inhibitor p27Kip1. In contrast, IL-6 failed to induce p21WAF1/CIP1 transcript and did not increase p21WAF1/CIP1 or p27kip1 proteins in any of the resistant lines. In fact, of five IL-6 resistant cell lines, only two expressed detectable levels of p21WAF1/CIP1 mRNA and protein, while in three other lines, p21WAF1/CIP1 was undetectable. IL-6 dependent upregulation of p21WAF1/CIP1 was associated with binding of both STAT3 and STAT1 to the p21WAF1/CIP1 promoter. Surprisingly, however, IL-6 stimulated STAT binding to this promoter in both sensitive and resistant cell lines (with one exception), suggesting that gross deregulation of this event is not the unifying cause of the defect in p21WAF1/CIP1 induction in IL-6 resistant cells. In somatic cell hybrids of IL-6 sensitive and resistant cell lines, the resistant phenotype was dominant and IL-6 failed to induce p21WAF1/CIP1. Thus, our results suggest that in early stage human melanoma cells, IL-6 induced growth inhibition involves induction of p21WAF1/CIP1 which is lost in the course of tumor progression presumably as a result of a dominant oncogenic event.
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PMID:Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. 1002 78

Because tumorigenesis frequently involves the dysfunction of cell cycle-related proteins, we examined the effect of mutations in CDK inhibitor p16 and its linked genomic loci p15, cl.B, and 1063.7 on the growth of primary adult T-cell leukemia (ATL) cells. Southern blot analysis of primary ATL cells showed a significantly higher incidence of p16 gene alteration in acute ATL than in chronic ATL [67.7% (23/34) vs. 26.1% (6/23), respectively; p<0.003]. Similarly, polymerase chain reaction (PCR) analysis of p16 exon 2 revealed a higher incidence of alteration in acute ATL than in chronic ATL [52.9% (18/34) vs. 26.1% (6/23), respectively; p<0.05]. PCR-single strand conformation polymorphism analysis of exons 1 and 2 of p16 showed no mutations in the patients, with normal pattern by Southern blotting or PCR analysis. Notably five of six chronic ATL patients with abnormal p16 genes progressed to acute crisis within 4 months. PCR analysis of the p16 linked loci 1063.7, p15 exon 2, and cl.B found homozygous deletion in 55.9%, 20.6%, and 2.9% of acute ATL cells and 39.1%, 13.0%, and 0% of chronic ATL cells, respectively, showing no relationship of homozygous deletion in either loci with disease subtypes. In most cases, deletions were seen in multiple genes, including p16. Acute ATL cells had a higher frequency of multigene deletions than chronic ATL cells [44.1% vs. 17.4%; p<0.05]. When leukemic cells were analyzed for interleukin 2 (IL-2) responsive growth, only p16 gene alteration was directly associated with leukemic cell growth activity. Among leukemic cells showing high IL-2 responsiveness, 73.1% (19/26) had p16 gene alteration vs. 27.8% (5/18) of leukemic cells that showed low IL-2 responsiveness (p<0.005). p16 gene alteration was found in 73.3% (14/19) of leukemic cells showing high autonomous growth rates but in only 40.0% (10/25) of those leukemic cells showing low autonomous growth (p<0.03). These results suggest the following: alteration of p16-related genomic regions in ATL is usually a wide rearrangement including the p16 gene; within this region, only p16 gene alteration is associated with disease aggressiveness; and p16 gene deletion may be a proximate event in leukemogenesis.
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PMID:Alteration of p16 (CDKN2) gene is associated with interleukin-2-induced tumor cell growth in adult T-cell leukemia. 1037 89

The cell cycle of cultured cells appears to be regulated by opposing actions of the cyclins together with their partners, the cyclin-dependent kinases (Cdk), and their inhibitors (Cki). Consistent with this situation null mutations in the genes for cyclin D1 and Cki p27(Kip1) in mice give opposite phenotypes of dwarfism and gigantism. To test their genetic interactions, we generated mice nullizygous for both genes. Correction of cyclin D1 or p27 null to wild-type phenotypes was observed for many but not all traits. These included, for cyclin D1(-/-) mice, body weight, early lethality, retinal hypoplasia, and male aggressiveness and, for p27(-/-) mice, body weight, retinal hyperplasia, and embryo implantation. p27(-/-) traits that were not corrected were the aberrant estrus cycles, luteal cell proliferation, and susceptibility to pituitary tumors. This mutual correction of these phenotypes is the first genetic demonstration of the interaction of these inhibitory and stimulatory cell cycle-regulatory molecules in vivo. The molecular basis for the correction was analyzed in the neonatal retina. Retinal cellularity was rescued in the cyclin D1 null mouse by loss of p27 with only a partial restoration of phosphorylation of retinoblastoma protein (Rb) and Cdk4 activity but with a dramatic elevation of Cdk2 activity. Our data provide in vivo genetic validation of cell culture experiments that indicated that p27 acts as a negative regulator of cyclin E-Cdk2 activity and that it can be titrated away by cyclin D-Cdk4 complexes. It also supports the suggestion that the cyclin E/Cdk2 pathway can largely bypass Rb in regulating the cell cycle in vivo.
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PMID:Genetic evidence for the interactions of cyclin D1 and p27(Kip1) in mice. 1115 17

Previous studies have demonstrated that cell proliferating activity accurately reflects the biological aggressiveness of thyroid neoplasms. In this study, we focused on the G2-M boundary regulators of the cell cycle and investigated the expression of three proteins, cyclin A, cyclin B1 and cdc2. The incidence of cyclin A overexpression was significantly linked to carcinoma differentiation (p < 0.0001) and, in particular, all 21 cases of undifferentiated carcinoma overexpressed this protein. On the other hand, cyclin B1 was overexpressed in four undifferentiated carcinomas (19.0%), but not in carcinomas of other types. Cdc2 overexpression was also related to carcinoma differentiation (p < 0.0001), and was directly linked to cyclin A overexpression (p < 0.0001), but not to cyclin B1 overexpression. No significant relationship could be established between the overexpression of these proteins and the histological type of follicular tumor. These results suggest that cyclin A, rather than cyclin B1, contributes significantly to the aggressive character of thyroid carcinoma, together with cdc2.
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PMID:Expression of G2-M modulators in thyroid neoplasms: correlation of cyclin A, B1 and cdc2 with differentiation. 1216 96

Despite improvement in surgical techniques, prognosis of gallbladder carcinoma remains poor. It is desirable to identify prognostic biomarkers to aid in the development of targeted therapeutic strategies. Two SCF(Skp2) ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in post-transcriptional degradation of p27(Kip1) tumor suppressor, which inhibits both cdk2/cyclin E and cdk2/cyclin A complexes and thus prevents transition to the S phase. However, the prognostic utility of p27(Kip1)-interacting cell cycle regulators has not been systematically assessed in gallbladder carcinoma. Immunohistochemistry was performed for p27(Kip1), Skp2, Cks1, cyclin E, cyclin A, and Ki-67 in tissue microarrays of 62 gallbladder carcinomas with follow-up. The data were correlated with clinicopathological features and overall survival (OS). The cumulative OS rate for all 62 cases was 42.9% at 3 years. Aberrant labeling indices (LIs) of p27(Kip1) (<20%), cyclin E (>or=5%), cyclin A (>or=5%), Cks1 (>or=40%), and Skp2 (>or=10%) were identified in 29, 58, 66, 21, and 57% of gallbladder carcinomas, respectively. By log-rank tests, downregulation of p27(Kip1) (P=0.0319) and high LIs of Skp2 (P=0.0006), Cks1 (P=0.0460), cyclin E (P=0.0070), and Ki-67 (P=0.0037) were predictive of inferior OS. Furthermore, the combined expression status of Skp2 and Ki-67 robustly defined three prognostically different groups (P=0.0001). In multivariate comparison, Skp2 overexpression represented the strongest independent adverse prognosticator (P=0.004, risk ratio (RR): 5.538), followed by Ki-67 LI >or=50% (P=0.016, RR: 3.254) and American Joint Committee on Cancer stages II-IV (P=0.013, RR: 3.163). In conclusion, aberrations of p27(Kip1)-interacting cell cycle regulators are common in gallbladder carcinomas. Skp2 overexpression is highly representative of biological aggressiveness and independently associated with poor OS, suggesting that it is a promising novel target for therapeutic intervention in aggressive cases. The combined assessment of Skp2 and Ki-67 LIs effectively risk-stratifies gallbladder carcinomas with different prognosis, which is worth being prospectively validated in future study.
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PMID:Skp2 is an independent prognosticator of gallbladder carcinoma among p27(Kip1)-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray. 1738 52

Cyclin B is the key regulatory protein controlling mitosis in all eukaryotes, where it binds cyclin-dependent kinase, cdk1, forming a complex which initiates the mitotic program through phosphorylation of select proteins. Cyclin B regulates the activation, subcellular localization, and substrate specificity of cdk1, and destruction of cyclin B is necessary for mitotic exit. Overexpression of human cyclin B1 has been found in numerous cancers and has been associated with tumor aggressiveness. Here we report the crystal structure of human cyclin B1 to 2.9 A. Comparison of the structure with cyclin A and cyclin E reveals remarkably similar N-terminal cyclin box motifs but significant differences among the C-terminal cyclin box lobes. Divergence in sequence gives rise to unique interaction surfaces at the proposed cyclin B/cdk1 interface as well as the 'RxL' motif substrate binding site on cyclin B. Examination of the structure provides insight into the molecular basis for differential affinities of protein based cyclin/cdk inhibitors such as p27, substrate recognition, and cdk interaction.
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PMID:The crystal structure of human cyclin B. 1749 33

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

Reduced expression of the CDK inhibitor p27(Kip1) (p27) in human lung cancer correlates with tumor aggressiveness and poor prognosis. However, the regulation of p27 expression and the role of p27 during lung cancer are poorly understood. Urethane-induced lung tumors in mice frequently harbor mutations in the Kras oncogene, and in this study, we use this model to address the regulation of p27 during tumorigenesis. The Ras effector Akt is known to regulate p27 mRNA abundance by phosphorylating and inactivating the FOXO transcription factors. Phosphorylated Akt and FOXO proteins were both increased in lung tumors, correlating with a reduction in p27 mRNA transcript. Akt also directly phosphorylates p27 and regulates its nuclear/cytoplasmic localization. Tumors showed a reduced nuclear/cytoplasmic ratio of p27 protein, together with an increase in phosphorylated Thr197 p27 in the cytoplasmic pool. Treatment of lung tumor-bearing mice with the phosphoinositol-3 kinase inhibitor LY294002 induced a rapid decrease in phosphorylated Akt and phosphorylated p27, concomitant with an increase in nuclear p27. Germline p27 deficiency accelerated both the growth and malignant progression of urethane-induced lung tumors, and did so in a cell autonomous manner, confirming a causal role of p27 in tumor suppression. These results show that p27 is a potent barrier to the growth and malignant progression of Kras-initiated lung tumors. Further, the reduction of nuclear p27 in tumors is mediated by oncogene signaling pathways, which can be reversed by pharmacological agents.
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PMID:Inhibition of PI-3K restores nuclear p27Kip1 expression in a mouse model of Kras-driven lung cancer. 1964 63


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