Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The abundance of p27(Kip1), an inhibitor of cell proliferation, is determined by Skp2-dependent proteolysis, the deregulation of which is associated with cancer progression. Lack of Skp2 results in p27(Kip1) accumulation as well as enlargement and polyploidy of hepatocytes. The role of Skp2 in cell growth and proliferation was investigated in Skp2-deficient mice subjected to partial hepatectomy. Skp2(-/-) mice exhibited restoration of liver mass without cell proliferation; rather, hepatocytes increased in size, an effect that was accompanied by increased polyploidy and p27(Kip1) accumulation. Lack of Skp2 thus impairs hepatocyte proliferation, which is compensated for by cellular enlargement, during liver regeneration.
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PMID:Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice. 1186 71

The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G1-S transition by controlling the stability of several G1 regulators, such as the cell cycle inhibitor p27kip1. However, the clinical significance of Skp2 in patients with laryngeal squamous cell carcinoma (LSCC) remains unknown. In this study, a potential distribution of Skp2 in LSCC and its clinical implications was investigated by an immunohistochemical study. Overall, Skp2 overexpression was observed in 36.7% (37 of 102) patients and was significantly associated with lymph node metastasis (p=0.002) and was inversely associated with p27kip1 expression (p=0.026). Survival analysis using the Kaplan-Meier method showed that Skp2 overexpression was significantly associated with shorter disease-free and overall survival (p=0.0051 and p=0.0002, respectively). When Skp2 expression and p27kip1 expression were combined, patients with both Skp2 overexpression and reduced expression of p27kip1 revealed poorest disease-free and overall survival as compared to the other cases (p=0.0017 and p<0.0001, respectively). Additionally, in early stage (I, II) cases, Skp2 expression was also revealed to possess a significant prognostic factor in overall survival (p=0.0234), but not in disease-free survival (p=0.2055). By multivariate analysis using the Cox proportional hazards model, tumor grade, tumor size, clinical stage and Skp2 expression were independent prognostic factors both in disease-free and overall survival. These findings indicated that Skp2 expression was closely associated with tumor progression and represented an independent marker for prognosis of LSCC.
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PMID:S-phase kinase-associated protein 2 expression in laryngeal squamous cell carcinomas and its prognostic implications. 1257 66

Autocrine motility factor (AMF)/phosphoglucose isomerase (PGI; EC 5.3.1.9) is a housekeeping cytosolic enzyme that plays a key role in both glycolysis and gluconeogenesis pathways. AMF/PGI is also a multifunctional protein that displays cytokine properties, eliciting mitogenic, motogenic, and differentiation activities, and has been implicated in tumor progression and metastasis. Because little is known about AMF/PGI-dependent signaling in general and during tumorigenesis in particular, we sought to study its effect on the cell cycle. To elucidate the functional role of PGI, we stably transfected its cDNA into NIH/3T3 and BALB/c 3T3-A31 fibroblasts. Ectopic overexpression of PGI results in the acquisition of a transformed phenotype associated with an acceleration of G1 to S cell cycle transition. These were manifested by up-regulation of cyclin D1 expression and cyclin-dependent kinase activity and down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. The reduced p27Kip1 protein expression level in PGI-overexpressing cells could be restored to control levels by treatment with proteasome inhibitor. PGI-overexpressing cells also exhibited elevated expression of Skp2 involved in p27Kip1 ubiquitination and elevation in the levels of retinoblastoma protein hyperphosphorylation. Thus, we may conclude that the overexpression of AMF/PGI enhances cell proliferation together with up-regulation of cyclin/cyclin-dependent kinase activities and down-regulation of p27Kip1, whereas the induction of 3T3 fibroblast transformation by PGI is regulated by the retinoblastoma protein pathway.
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PMID:Regulation of cell proliferation by autocrine motility factor/phosphoglucose isomerase signaling. 1278 64

It is believed that Rb blocks G1-S transition by inhibiting expression of E2F regulated genes. Here, we report that the effects of E2F repression lag behind the onset of G1 cell cycle arrest in timed Rb reexpression experiments. In comparison, kinase inhibitor p27Kip1 protein accumulates with a faster kinetics. Conversely, Rb knockout leads to faster p27 degradation. Rb interacts with the N terminus of Skp2, interferes with Skp2-p27 interaction, and inhibits ubiquitination of p27. Disruption of p27 function or expression of the Skp2 N terminus prevents Rb from causing G1 arrest. A full-penetrance, inactive Rb mutant fails to interfere with Skp2-p27 interaction but, interestingly, a partial-penetrance Rb mutant that is defective for E2F binding retains full activity in inhibiting Skp2-p27 interaction and can induce G1 cell cycle arrest with wild-type kinetics. These results identify an Rb-Skp2-p27 pathway in Rb function, which may be involved in inhibition of tumor progression.
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PMID:An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. 1546 21

The expression of cyclooxygenase (COX)-2 is induced by growth factors, tumor promoters and cytokines, and is correlated with carcinogenesis, tumor progression and inhibition of apoptosis. To clarify the pathological significance of COX-2, we examined the effect of a selective COX-2 inhibitor, NS398, on two human gastric carcinoma cell lines, MKN-45 and KATO-III, and the expression of Skp2, P27/Kip1 and COX-2 protein in human gastric carcinomas. NS398 inhibited cell growth in a time- and dose-dependent manner and exerted cell cycle arrest in the G0/G1 phase without induction of apoptosis in MKN-45, but had no effect in KATO-III. In MKN-45, NS398 induced up-regulation of P27/Kip1 and down-regulation of COX-2, cyclin D1 and Skp2. Immunohistochemistry using 63 surgically resected gastric carcinomas disclosed that COX-2 expression was correlated with Skp2 expression and that P27/Kip1 expression was inversely correlated with COX-2 and Skp2 expression. High levels of COX-2 or Skp2 were significantly correlated with poor survival (P=0.02 and P=0.004). Our results suggested that: a) NS398 induced inhibition of cell proliferation through cell cycle arrest and suppressed the expression of Skp2 in COX-2-expressing gastric carcinoma cells, and b) COX-2 contributes to the expression of Skp2 and poor survival in human gastric carcinomas.
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PMID:COX-2 correlates with F-box protein, Skp2 expression and prognosis in human gastric carcinoma. 1564 19

A well-established biological activity of the tumor suppressor Rb is blocking G1/S cell cycle progression when reintroduced into cultured Rb-deficient tumor cells. The best understood molecular mechanism underlying this function is that Rb binds the transcription factor E2F to repress expression of S phase genes such as cyclins E and A. A recent kinetic study of this model further revealed that Rb represses Skp2 to stabilize p27, which inhibits the kinase activity associated with cyclins E and A before the decline in their protein levels, to arrest the cell cycle. This p27-stabilizing function of Rb is retained in a clinical partial penetrance Rb mutant that is biochemically inactive for E2F repression, suggesting a mechanism for Rb-mediated inhibition of tumor progression.
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PMID:Using kinetic studies to uncover new Rb functions in inhibiting cell cycle progression. 1570 69

p27Kip1, an inhibitor of cyclin-dependent kinases, is a negative cell cycle regulator that plays an important role in tumor suppression. Deregulation of p27 is commonly observed in many human cancers secondary to enhanced ubiquitin-mediated degradation, mediated and rate-limited by its specific ubiquitin ligase subunits Skp2 and Cks1. In the present study the prognostic implications of p27 and the mechanisms that down-regulate its expression in colorectal cancer (CRC) are reviewed. A review and analysis of the English literature was conducted. Loss of p27 was strongly associated with aggressive tumor behavior and poor clinical outcome in CRC. Overexpression of Skp2 and Cks1 was observed in aggressive CRC and is responsible for down-regulation of p27 levels. Both Skp2 and Cks1 were found to be independent prognostic markers for survival and provide predictive information additional to that provided by p27 alone. Deregulation of p27 has a profound effect on tumor progression in CRC and was found to be an accurate and independent prognostic marker. Thus, determination of levels of p27 and of its ubiquitin ligase subunits by readily available immunohistochemical studies may be a useful tool in the assessment of prognosis, especially in patients with intermediate disease, and may potentially assist in the planning of adjuvant therapy and development of novel interventional therapy.
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PMID:Prognostic role of p27Kip1 deregulation in colorectal cancer. 1682 82

The expression of Skp2, the ubiquitin ligase subunit that targets p27(Kip1) for degradation, is commonly overexpressed in human cancers. p27(Kip1) is a negative regulator of the cell cycle that plays an important role in tumor suppression. Loss of p27(Kip1) secondary to enhanced ubiquitin-mediated degradation results in uncontrolled proliferation and promotes tumor progression. In the present study the prognostic implications of Skp2 are reviewed and the mechanisms that regulate its expression in different human cancers. A review and analysis of the English literature was undertaken. Overexpression of Skp2 mRNA and protein levels was observed in many aggressive cancers and was commonly associated with down-regulation of p27(Kip1) levels and loss of tumor differentiation. Skp2 is an independent prognostic marker for disease-free and overall survival and may provide additional predictive information to that provided by p27(Kip1) alone. Targeting Skp2 in experimental models resulted in up-regulation of p27(Kip1) and arrested cellular proliferation. Alterations in Skp2 expression have profound effects on cancer progression and may serve as an accurate and independent prognostic marker. Thus, determination of levels of Skp2 and p27(Kip1) by readily available immunohistochemical studies may be a useful tool in the assessment of prognosis, especially in patients with intermediate disease, and may potentially assist in the planning of adjuvant therapy. Skp2 may be an attractive target for the development of novel interventional therapy.
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PMID:Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer. 1826 93

Deregulated Skp2 function promotes cell transformation, and this is consistent with observations of Skp2 overexpression in many human cancers. However, the mechanisms underlying elevated Skp2 expression are still unknown. Here we show that the serine/threonine protein kinase Akt1, but not Akt2, directly controls Skp2 stability by a mechanism that involves degradation by the APC-Cdh1 ubiquitin ligase complex. We show further that Akt1 phosphorylates Skp2 at Ser 72, which is required to disrupt the interaction between Cdh1 and Skp2. In addition, we show that Ser 72 is localized within a putative nuclear localization sequence and that phosphorylation of Ser 72 by Akt leads to cytoplasmic translocation of Skp2. This finding expands our knowledge of how specific signalling kinase cascades influence proteolysis governed by APC-Cdh1 complexes, and provides evidence that elevated Akt activity and cytoplasmic Skp2 expression may be causative for cancer progression.
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PMID:Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction. 1933 20

The regulation of cell cycle entry is critical for cell proliferation and tumorigenesis. One of the key players regulating cell cycle progression is the F-box protein Skp2. Skp2 forms a SCF complex with Skp1, Cul-1, and Rbx1 to constitute E3 ligase through its F-box domain. Skp2 protein levels are regulated during the cell cycle, and recent studies reveal that Skp2 stability, subcellular localization, and activity are regulated by its phosphorylation. Overexpression of Skp2 is associated with a variety of human cancers, indicating that Skp2 may contribute to the development of human cancers. The notion is supported by various genetic mouse models that demonstrate an oncogenic activity of Skp2 and its requirement in cancer progression, suggesting that Skp2 may be a novel and attractive therapeutic target for cancers.
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PMID:Regulation of Skp2 expression and activity and its role in cancer progression. 2052 32


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