Inverse relation between levels of p27Kip1 and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas

Hershko, Dan; Bornstein, Gil; Ben‐Izhak, Ofer; Carrano, Andrea C.; Pagano, Michele; Krausz, Michael M.; Hershko, Avram

doi:10.1002/1097-0142(20010501)91:9<1745::aid-cncr1193>3.0.co;2-h

Cited by 153 publications

(125 citation statements)

References 15 publications

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“…3). In particular, Skp2 levels have been examined in human tumors and have been shown to correlate with grade of malignancy [51,[53][54][55][56][57]69,70]. Similar findings have been reported for high levels of cyclin E and A (reviewed in [58]).…”

Section: P27 and Human Cancersmentioning

confidence: 69%

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Bloom

Pagano

2003

Seminars in Cancer Biology

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335

317

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Section: P27 and Human Cancersmentioning

confidence: 69%

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Bloom

Pagano

2003

Seminars in Cancer Biology

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335

317

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“…A strong correlation was found between Skp2 and Cks1 expression (r ϭ 0.264; P ϭ 0.02), and both proteins were inversely related to p27 Kip1 levels (r ϭ Ϫ0.315; Pϭ0.005, and r ϭ Ϫ0.242; P ϭ 0.034, respectively), similar to previous findings from our laboratory. 13,16 The clinical and histologic data, and the immunohistochemical analyses of the study patients are summarized in Table 1. Skp2, Cks1, and p27 Kip1 expressions were not associated with patients' age or gender (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…The specificity of immunohistochemistry staining for Skp2, Cks1, and p27 Kip1 was previously verified by comparing the expression of the proteins on immunohistochemistry with protein levels determined by immunoblot analysis from the same tumor specimens. 13,16 Grading of nuclear protein staining was also based on previous experiments from our laboratory and were compared with immunoblot analysis for semiquantification as high or low. 13,16 In brief, nuclear protein expression of epithelial cells only was scored as high if 50% or more of the nuclei were stained or low if less than 50% were stained.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…13,16 Grading of nuclear protein staining was also based on previous experiments from our laboratory and were compared with immunoblot analysis for semiquantification as high or low. 13,16 In brief, nuclear protein expression of epithelial cells only was scored as high if 50% or more of the nuclei were stained or low if less than 50% were stained. When stained, cells displayed similar intensity of nuclear staining regardless of the percentage of cell stained, and, therefore, the intensity of staining was not included in the score.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…In a recent study from our laboratory, the authors of the current study provided data to support the hypothesis that the decrease in p27 Kip1 protein levels in aggressive colorectal carcinomas is Skp2-dependent. 13 A strong inverse relation was found between p27 Kip1 and Skp2 levels in tumor specimens obtained from colorectal carcinoma patients. Thus, decreased levels of p27 Kip1 were associated with increased levels of Skp2, whereas low levels of Skp2 coincided with high levels of p27 Kip1 .…”

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confidence: 95%

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The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

Shapira

Ben‐Izhak

Linn

et al. 2005

Cancer

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126

112

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BACKGROUNDLoss of the cell‐cycle inhibitory protein p27Kip1 is associated with poor prognosis in colorectal carcinoma. The decrease in p27Kip1 levels is the result of increased proteasome‐dependent degradation, mediated and rate‐limited by its specific ubiquitin ligase subunits S‐phase kinase protein (Skp) 2 and cyclin‐dependent kinase subunit (Cks) 1. Recently, Skp2 and Cks1 expression were found to be increased in some colorectal carcinomas, but their potential role as prognostic markers for survival is unknown. The present study was undertaken to assess the prognostic value of both Skp2 and Cks1 in colorectal carcinoma.MATERIALS AND METHODSThe expression of Skp2, Cks1, and p27Kip1 was examined by immunohistochemistry using highly specific antibodies on formalin‐fixed, paraffin‐embedded tissue sections from 80 patients with colorectal carcinoma.RESULTSOverexpression of Skp2 and Cks1 strongly correlated with loss of p27Kip1 and loss of tumor differentiation. A significant decrease in overall survival was observed in patients expressing high Skp2 or Cks1 levels, and in particular, patients with Stage II and III disease. Each protein provided significant additional prognostic information to that given by disease stage, tumor grade, or p27Kip1 expression.CONCLUSIONSResults suggest that overexpression of Skp2 or Cks1 is strongly associated with poor prognosis and may thus be used as prognostic markers for overall survival in colorectal carcinoma. Cancer 2005. © 2005 American Cancer Society.

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Alterations in the expression of the cell cycle regulatory protein cyclin kinase subunit 1 in colorectal carcinoma

Shapira

Ben‐Izhak

Bishara

et al. 2004

Cancer

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BACKGROUND Low levels of p27Kip1 are associated with high aggressiveness and poor prognosis in various malignancies, including colorectal carcinoma. The authors showed that S phase kinase protein 2 (Skp2), the specific ubiquitin ligase subunit that targets p27Kip1 for degradation, was overexpressed and was inversely related to p27Kip1 levels in patients with colorectal carcinoma. The essential role of cyclin kinase subunit 1 (Cks1) in Skp2‐dependent p27 degradation was recently discovered, but its role in human malignancies is unknown. METHODS Quick‐frozen colorectal tumor samples from 30 patients were separated by electrophoresis on sodium dodecyl sulfate–polyacrylamide gels, transferred to nitrocellulose, and probed with highly specific monoclonal antibodies directed against Cks1, Skp2, and p27Kip1. The expression of Cks1 was also examined by immunohistochemistry using formalin‐fixed, paraffin‐embedded tissue sections from the same patients. RESULTS A strong correlation was found between Cks1 levels and Skp2 expression and loss of tumor differentiation. A significant inverse relation was also observed between levels of Cks1 and p27Kip1 and overall survival. CONCLUSIONS The results of the current study suggest that increased expression of Cks1 may have an important causative role in decreasing levels of p27 in patients with aggressive colorectal carcinoma. Cancer 2004. © 2004 American Cancer Society.

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Inverse relation between levels of p27Kip1 and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas

Cited by 153 publications

References 15 publications

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

Alterations in the expression of the cell cycle regulatory protein cyclin kinase subunit 1 in colorectal carcinoma

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