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 signal transduction pathway regulated by the retinoblastoma tumor suppressor protein, pRB, is abrogated in the majority of human cancers. Using a series of cell lines derived from oral squamous cell carcinomas (SCCs) that were not subjected to radiation or chemotherapy treatment, we detected specific hyperactivity of cyclin dependent kinase (cdk) 6 but not cdk4. Subcellular localization studies showed a predominant nuclear localization of cdk6, demonstrating that this kinase was biologically active. The molecular basis for this aberration are mutations in the MTS1 locus of chromosome 9p21. This locus encodes two partially overlapping genes, the cdk inhibitor p16(ink4a), and p14(ARF), an inhibitor of mdm2-mediated degradation of p53. Our analysis demonstrates that the mutations of the MTS1 locus in oral SCC specifically target expression of the p16(ink4a) gene but less frequently affect p14(ARF). These results suggest that hyperactivity of cdk6 represents a distinct mechanism for pRB inactivation in oral SCC.
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PMID:Aberrations in the MTS1 tumor suppressor locus in oral squamous cell carcinoma lines preferentially affect the INK4A gene and result in increased cdk6 activity. 1185 66

Using alternative reading frames, the human ARF-INK4a locus encodes two unrelated proteins that both function in tumor suppression. p16(INK4a) maintains the retinoblastoma protein in its growth-suppressive state through inhibition of cyclin D-dependent kinase activity, whereas ARF binds with MDM2 and stabilizes p53. The majority of the activity of ARF to date is ascribed to its ability to activate p53, resulting in a G(1) cell cycle arrest or apoptosis. We show here that ARF colocalizes with DNA replication protein A (RPA32) and that overexpression of ARF reduces the rate of DNA synthesis resulting in accumulation of an S-phase cell population. Impediment of DNA synthesis by ARF can occur and becomes more evident in the absence of p53. Hence, the biological consequence of ARF induction varies dependent on cellular p53 status, inducing predominantly a G(1) arrest or apoptosis in p53-positive cells or causing S-phase retardation when p53 function is comprised.
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PMID:Human tumor suppressor ARF impedes S-phase progression independent of p53. 1186

Granulosa cell tumors (GCTs) of the ovary are relatively rare and account for <5% of all ovarian cancers. The molecular pathogenesis of these tumors is not well understood. We tested the hypothesis that cyclin-dependent kinase inhibitors, specifically the inhibitors of the cyclin-dependent kinase 4 (INK4) family, are targets for altered gene expression in GCTs. The status of RB1, INK4A, INK4B, INK4C, INK4D, and ARF in 13 adult and 2 juvenile ovarian GCTs was determined by reverse transcription-polymerase chain reaction of total RNA and exon-specific sequencing of genomic DNA. Tumors showing loss of INK4A expression were assayed further by exon-deletion analysis and methylation-specific PCR. None of the juvenile tumors demonstrated altered expression, but 7/12 (58%) adult GCTs lacked expression of INK4A, INK4B, or both. In one of these cases, we noted a homozygous deletion of the INK4A locus, and in the remaining tumors we found hypermethylation of the promoter region, a mechanism that can lead to gene inactivation. These data support a role for the INK4 family of CDK inhibitors in the biology of GCTs.
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PMID:Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors. 1220 82

Epidemiological studies support a link between melanoma risk and UV exposure early in life, yet the molecular targets of UV's mutagenic actions are not known. By using well characterized murine models of melanoma, we provide genetic and molecular evidence that identifies components of the Rb pathway as the principal targets of UV mutagenesis in murine melanoma development. In a melanoma model driven by H-RAS activation and loss of p19(ARF) function, UV exposure resulted in a marked acceleration in melanoma genesis, with nearly half of these tumors harboring amplification of cyclin-dependent kinase (cdk) 6, whereas none of the melanomas arising in the absence of UV treatment possessed cdk6 amplification. Moreover, UV-induced melanomas showed a strict reciprocal relationship between cdk6 amplification and p16(INK4a) loss, which is consistent with the actions of UV along the Rb pathway. Most significantly, UV exposure had no impact on the kinetics of melanoma driven by H-RAS activation and p16(INK4a) deficiency. Together, these molecular and genetic data identify components of the Rb pathway as critical biological targets of UV-induced mutagenesis in the development of murine melanoma in vivo.
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PMID:Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model. 1253 79

The astrocytomas represent the most common primary tumors of the brain. Despite efforts to improve the treatment of astrocytomas, these tumors and in particular the high-grade astrocytoma termed glioblastoma multiforme still carry a poor prognosis. In recent years, there has been an intensive effort to gain an understanding of the cellular and molecular mechanisms that contribute to the pathogenesis of astrocytomas as a first step toward the development of better treatments for these devastating tumors. Here, we will review our current understanding of the signaling pathways that underlie glial transformation. Studies of astrocytomas have led to the identification of two major groups of signaling proteins whose abnormalities contribute to gliomagenesis: the cell cycle pathways and the growth factor-regulated signaling pathways. Among the cell cycle proteins, the p16-cdk4-pRb and ARF-MDM2-p53 cell cycle arrest pathways play a prominent role in glial transformation. In addition, deregulation of polypeptide growth factors acting via receptor tyrosine kinases (RTKs) and of intracellular signals, including the lipid phosphatase PTEN, that regulate cellular responses to RTKs plays a critical role in gliomagenesis. In addition to the identification of the signaling proteins targeted in glial transformation, the cell-of-origin of astrocytomas has been investigated. Genetic modeling of astrocytomas in mice suggests that neuroepithelial precursor cells represent preferred cellular substrates of gliomas or that either astrocytes or precursor cells constitute potential cells-of-origin of astrocytomas. During normal brain development, neuroepithelial precursor cells, including neural stem cells, differentiate into astrocytes. As the mechanisms that control gliogenesis during normal brain development become better understood, it will be important to determine if deregulation of these mechanisms might contribute to the pathogenesis of astrocytomas. The elucidation of the molecular underpinnings of astrocytomas holds the promise of improved treatment options for patients with these devastating brain tumors.
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PMID:Signaling pathways regulating gliomagenesis. 1255 76

Until recently, the ability of ARF (human p14(ARF), murine p19(ARF)) tumour-suppressor protein, encoded by the INK4A/ARF locus, to inhibit cell growth in response to various stimuli was related to its ability to stabilize p53 through the so-called ARF/MDM2/p53 pathway. However, recent data have demonstrated that ARF is not implicated in this unique p53-dependent pathway. By use of transient and stable expression, we show here that human p14(ARF) inhibits the growth of human tumoral cells lacking functional p53 by inducing a transient G(2) arrest and subsequently apoptosis. This p14(ARF)-induced G(2) arrest was correlated with inhibition of CDC2 activity, inactivation of CDC25C phosphatase and induction of the CDK inhibitor p21(WAFI). Apoptosis was demonstrated using Hoechst 33352 staining, proteolytic activation of caspase-3 and PARP cleavage. Similar results were obtained in experiments with cells synchronized by hydroxyurea block. Importantly, we were able to reproduce these effects 'in vivo' by showing that p14(ARF) inhibits the growth of p53 nullizygous human tumours in nude mice and induces the regression of p53 -/- established tumours. In these experiments, tumoral regression was associated with inhibition of cell proliferation as well as induction of apoptosis confirming the data obtained in cell lines.
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PMID:p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. 1266 Aug 18

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

The tumor suppressor p14(ARF) gene is induced by ectopically expressed E2F, a positive regulator of the cell cycle. The gene is expressed at low levels in normally growing cells in contrast to high levels in varieties of tumors. How p14(ARF) gene is regulated by E2F in normally growing cells and tumor cells remains obscure. Here we show that regulation of p14(ARF) gene by E2F is distinct from that of classical E2F targets. It is directly mediated by E2F through a novel E2F-responsive element that varies from the typical E2F site. The element responds to E2F activity resulting from ectopic E2F1 expression, inactivation of pRb by adenovirus E1a or shRNA, but not to phosphorylation of pRb by serum stimulation or ectopic cyclin D1/cyclin-dependent kinase-4 expression in normal human fibroblasts. The element has activity in various tumor cells with defective pRb, but not in normally growing cells. These results indicate that the distinct regulation constitutes the basis of p14(ARF) function as a tumor suppressor, discriminating abnormal growth signals caused by defects in pRb function from normal growth signals.
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PMID:Distinct E2F-mediated transcriptional program regulates p14ARF gene expression. 1621 Oct 8

Malignant pleural mesothelioma, although uncommon, is highly lethal. There is a high correlation between associated environmental exposure factors, carcinogens, and its development. Carcinogenesis is also mediated by genetic defects that result in loss of tumor suppressors or over expression of proto-oncogenes. Factors such as the loss of CDK inhibition function, IGF stimulatory pathways, p14(ARF), p15(INK4b), p16(INK4a), p21, and p53 loss or mutation, VEGF and COX over expression are discussed. Correlations to potential therapeutic modalities are made.
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PMID:Molecular pathways in malignant pleural mesothelioma. 1621 11

The most common genetic damage in urothelial carcinoma is partial loss of chromosome 9. The area around 9p21 where the CDKN2A/ARF gene is located is one of the major sites for deletion. This gene encodes for p16 protein which impedes the cell cycle. Specific binding of the p16 product to the cyclin-dependent protein kinases cdk4 or cdk6 inhibits the catalytic activity of the cyclin D-cdk complex, and consequently arrests the cell cycle at the G1/G2 phase. This study aims to immunohistochemically assess p16 expression in urothelial carcinoma in order to evaluate the correlation of this biological marker with tumour stage and/or grade. We studied specimens of transurethral resection (TURB) from 17 cases of non-invasive papillary urothelial carcinoma and from 22 cases of invasive urothelial carcinoma of the bladder. We observed strong p16 immunoreactivity in 11 cases (28.2%), while 28 cases (71.8%) did not show p16 staining. The expression of p16 was statistically associated with disease stage (p = 0.026, according to the chi-square test), but not with either tumour grade or disease progression. These observations call for further studies to focus the importance of p16 expression in bladder cancer development and/or progression. Additional data may provide insight into treatment guided by molecular changes.
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PMID:p16(INK4a) expression in urinary bladder carcinoma. 1713 23


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