The expression of the ubiquitin ligase subunit Cks1 in human breast cancer

Slotky, Merav; Shapira, Maanit; Ben‐Izhak, Ofer; Linn, Shai; Futerman, Boris; Tsalic, Medy; Hershko, Dan

doi:10.1186/bcr1278

Cited by 80 publications

(71 citation statements)

References 23 publications

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“…37 Additionally, in vitro models have identified Cks1 as an essential cofactor for efficient Skp2-dependent ubiquitination of p27 Kip126 and its overexpression was found strongly associated with poor prognosis in carcinomas of the colorectum, stomach, and breast. 28,29,38 Furthermore, gene amplification and overexpression of Cks1 at chromosome band 1q21 is associated with reduced levels of p27 Kip1 and an aggressive clinical course in multiple myeloma. 39 In our univariate analysis, Cks1 overexpression also correlated with inferior OS in gallbladder carcinomas, although it did not remain prognostically independent in multivariate comparison.…”

Section: Skp2 Asmentioning

confidence: 99%

Skp2 is an independent prognosticator of gallbladder carcinoma among p27Kip1-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray

Sung

et al. 2007

Modern Pathology

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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 posttranscriptional degradation of p27Kip1 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 (o20%), cyclin E (Z5%), cyclin A (Z5%), Cks1 (Z40%), and Skp2 (Z10%) were identified in 29, 58, 66, 21, and 57% of gallbladder carcinomas, respectively. By log-rank tests, downregulation of p27 Kip1 (P ¼ 0.0319) and high LIs of Skp2 (P ¼ 0.0006), Cks1 (P ¼ 0.0460), cyclin E (P ¼ 0.0070), and Ki-67 (P ¼ 0.0037) were predictive of inferior OS. Furthermore, the combined expression status of Skp2 and Ki-67 robustly defined three prognostically different groups (P ¼ 0.0001). In multivariate comparison, Skp2 overexpression represented the strongest independent adverse prognosticator (P ¼ 0.004, risk ratio (RR): 5.538), followed by Ki-67 LI Z50% (P ¼ 0.016, RR: 3.254) and American Joint Committee on Cancer stages II-IV (P ¼ 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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Section: Skp2 Asmentioning

confidence: 99%

Skp2 is an independent prognosticator of gallbladder carcinoma among p27Kip1-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray

Sung

et al. 2007

Modern Pathology

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“…Increases in Cks1 expression have been shown in a number of human malignancies (1)(2)(3)(4). Increase in Cks1 mRNA has also been shown in PyMT-initiated mammary tumors (17), and in urethane and ENU-initiated lung tumors in rasH2 mice (32).…”

Section: Discussionmentioning

confidence: 96%

“…Kip1 (1). Interestingly, high expression of Cks1 has also been reported in non-small cell lung carcinomas, although it was not inversely related with p27 Kip1 expression, suggesting that Cks1 may mediate some of its functions via Skp2 and p27 Kip1 -independent mechanisms (3).…”

Section: Introductionmentioning

confidence: 99%

“…Cyclin kinase subunit 1 (Cks1) is a small protein whose expression is strongly associated with aggressive breast tumors, prostate carcinomas, non-small cell lung cancers, and several other malignancies (1)(2)(3)(4). Cks1 was shown to associate with Skp2, a subunit of the SCF Skp2 ubiquitin ligase which mediates the ubiquitin-dependent proteolysis of the cdk inhibitor p27…”

Section: Introductionmentioning

confidence: 99%

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High Cks1 expression in transgenic and carcinogen-initiated mammary tumors is not always accompanied by reduction in p27Kip1

Westbrook

Ramanathan²,

Isayeva³

et al. 2009

Int J Oncol

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Abstract. Cks1 plays an essential role in SCFSkp2 -mediated ubiquitination, and consequently turnover, of the cdk2 inhibitor and tumor supressor p27 Kip1 . High Cks1 expression is associated with aggressive breast tumors and correlates with low p27Kip1 levels in some cases, although it is also an independent prognostic marker for survival, and provides predictive information in addition to that provided by p27 Kip1 alone. In this report we demonstrate that Cks1 protein and mRNA are elevated to very high levels in mammary tumors initiated by erbB2, c-myc and polyoma middle-T (PyMT) in transgenic mice, whereas Cks1 protein is hardly detectable in the normal mammary epithelium. Cks1 is also highly upregulated in rat mammary tumors initiated by methylnitrosourea (MNU). Despite high levels of Cks1 expression, p27 Kip1 levels were not reduced, and were in fact slightly higher in mammary tumors initiated by erbB2, PyMT and MNU. In contrast mammary tumors from MMTV-c-myc mice did exhibit low p27Kip1 and higher levels of Skp2. Together, these data suggest that deregulated Cks1 expression might play roles in oncogene and carcinogen-initiated mammary tumorigenesis independent of p27 Kip1 turnover in certain tumors. Stable overexpression of Cks1 in human breast carcinoma MCF-7 cells did not significantly reduce p27 Kip1 expression, although it conferred resistance to Faslodex (ICI 182780)-mediated inhibition of colony outgrowth in these cells. In contrast, Cks1-depleted MCF-7 cells formed fewer colonies in estrogen-containing medium. Therefore, our studies also suggest that Cks1 levels regulate the responsiveness of ER + breast cancers to estrogens and anti-estrogens.

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“…In fact, overexpression of Skp2 and/or Cks1 has been found in breast cancer tissues and is an independent prognostic marker for disease-free and overall survival and is associated with aggressiveness (5-9). In cell culture, higher expression levels of Skp2 were found in estrogen receptor (ER)/Her2-negative aggressive breast cancer cells, such as MDA-MB-231, as compared to MCF-7 ER-positive breast cancer cells (6,7).…”

Section: Introductionmentioning

confidence: 99%

Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells

2012

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Abstract. Vorinostat is a histone deacetylase inhibitor that blocks cancer cell proliferation through the regulation of cyclin-dependent kinase inhibitors. We, herein, examined the involvement of S-phase kinase-associated protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1), the components of the SCF Skp2-Cks1 (Skp1/Cul1/F-box protein) ubiquitin ligase complex, in the regulation of p27 and p21 during vorinostatinduced growth arrest of MDA-MB-231 and MCF-7 human breast cancer cells. Vorinostat significantly reduced BrdU incorporation in MDA-MB-231 and MCF-7 cells, which was associated with increased p27 and p21 protein levels without concomitant induction of p27 mRNA. Vorinostatinduced accumulation of p27 and p21 proteins was inversely correlated with the mRNA and protein levels of Skp2 and Cks1. Cycloheximide chase analysis revealed that vorinostat increased the half-life of p27 and p21 proteins. The accumulation of p27 and p21 proteins was attenuated by forced expression of Skp2 and Cks1, which conferred resistance to the vorinostat-induced S-phase reduction. These results suggest that vorinostat-induced growth arrest may be in part due to the enhanced protein stability of p27 and p21 through the downregulation of Skp2 and Cks1. IntroductionCell cycle progression is tightly controlled by the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs), such as p27 and p21 (1). Timely degradation of these proteins is required for proper cell-cycle progression. S-phase kinase associated protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1) are the subunits of the SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complex that are responsible for S-phase entry through the ubiquitination of p27 and p21, which is followed by their degradation by the proteasome pathway (2). Many cancer cells exhibit abnormal proliferation that is attributed to aberrant cell cycle progression. Numerous studies have reported the loss of p27 in a wide variety of malignancies including breast cancer (3,4). The loss of p27 was due to accelerated degradation by the ubiquitin-proteasome pathway, rather than transcriptional repression. In fact, overexpression of Skp2 and/or Cks1 has been found in breast cancer tissues and is an independent prognostic marker for disease-free and overall survival and is associated with aggressiveness (5-9). In cell culture, higher expression levels of Skp2 were found in estrogen receptor (ER)/Her2-negative aggressive breast cancer cells, such as MDA-MB-231, as compared to MCF-7 ER-positive breast cancer cells (6,7).Vorinostat is a potent histone deacetylase inhibitor (HDACi) that exerts antitumor effects by inducing differentiation, growth arrest and/or apoptosis through acetylation modification of histones and/or non-histone proteins (10). Vorinostat induces cell-cycle arrest at the G1 or the G2/M boundary in a cell-type dependent and/or dose-related fashion (11). The transactivation of CDKN1A, which encodes p21, is commonly observed after HDACi treatment (12). In addition, induction ...

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The expression of the ubiquitin ligase subunit Cks1 in human breast cancer

Cited by 80 publications

References 23 publications

Skp2 is an independent prognosticator of gallbladder carcinoma among p27Kip1-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray

Skp2 is an independent prognosticator of gallbladder carcinoma among p27Kip1-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray

High Cks1 expression in transgenic and carcinogen-initiated mammary tumors is not always accompanied by reduction in p27Kip1

Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells

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