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

Shapira, Maanit; Ben‐Izhak, Ofer; Linn, Shai; Futerman, Boris; Minkov, Ira; Hershko, Dan

doi:10.1002/cncr.20917

Cited by 132 publications

(129 citation statements)

References 22 publications

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“…97 Skp2/Cks1 are inversely related in Cks1 and Skp2 null animals 30,84 and many human cancers. 46,[85][86][87][88] Moreover, B-RAF and cyclin D1 upregulate Cks1 and Skp2, and Myc induces Cks1 for p27 degradation in certain human cancers. 89,90 Our data demonstrate that 4 hr after treatment with TGFβ, Cks1 mRNA is slightly upregulated and then decreased to basal levels by 24 hr.…”

Section: © 2 0 0 9 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Lecanda

Ganapathy²,

D'Aquino-Ardalan³

et al. 2009

Cell Cycle

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TGFβ mediates cell cycle arrest in late G 1 phase of the cell cycle with a simultaneous peak in the levels of the cyclin-dependent kinase inhibitor, p27 kip1 (p27). In this report, we show that whereas p27 resides in the cytoplasm in the endometrial carcinoma (ECA) cell line HEC-1A, TGFβ increases the total levels and translocation of p27 into the nucleus. Concomitantly, TGFβ activates the transcription factors Smad2 and Smad3, inhibits proliferation, and blocks Cdk2 activity; all these events are blocked by an inhibitor of TβRI serine kinase activity (SD208). In addition, we show that inhibiting p27 transcription with a specific siRNA completely blocks TGFβ-mediated growth inhibition in these cells. These data suggest that TGFβ inhibits cellular proliferation by increasing p27 levels through Smad2/3 signaling in HEC-1A cells. We further show that TGFβ decreases the levels of components of the SCF Skp2 targeting complex for ubiquitin-mediated degradation of p27 in proteasomes, at the protein but not the mRNA level. Therefore, TGFβ accumulates nuclear p27 by preventing its degradation to enable G 1 arrest in HEC-1A cells. Importantly, these data suggest a novel mechanism for TGFβ/Smad mediated growth inhibition that might be inoperable in the numerous human cancers demonstrating early dysregulated TGFβ signaling and loss of growth inhibition. The TGFβ/p27 axis might provide novel therapeutic targets for cancer.

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Section: © 2 0 0 9 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Lecanda

Ganapathy²,

D'Aquino-Ardalan³

et al. 2009

Cell Cycle

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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: 95%

“…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%

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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“…The discovery of useful molecular markers involved in crucial steps of carcinogenesis provides information on MST behavior, yet applying their use to the understanding of histogenesis is less common. Human cancer, manifested as uncontrolled cellular proliferation, is commonly caused by changes in the expression or activity of proteins involved in regulating the normal cell cycle [13]. p27, a member of the cip/kip family of cyclin-dependent kinase inhibitors, is expressed at high levels in G o cells and promotes cell arrest and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…p27, a member of the cip/kip family of cyclin-dependent kinase inhibitors, is expressed at high levels in G o cells and promotes cell arrest and apoptosis. The protein that specifically binds and targets p27 for degradation is S-phase kinase associated protein-2 (skp-2), and may be the main rate-limiting regulator for p27 degradation [13]. Previous studies on a variety of human cancers showed that an altered p27/skp-2 ratio was associated with poorer differentiation, aggressive biological behavior and worse clinical outcome [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

P27/SKP-2 Histochemical Profile is Relevant to Malignant Salivary Gland Tumors (MST) Histogenesis and Tumor Grade

Akrish

Ben‐Izhak

Peled

2011

Head and Neck Pathol

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Malignant salivary gland tumors (MST) represent over more than 24 distinct morphological subtypes. Most high grade tumors arise from the excretory duct portion of the salivary gland apparatus; the remainder from the intercalated duct portion. Altered p27/skp-2 expression has been associated with tumor aggressiveness and histologic differentiation. In our study, we analyzed p27/skp-2 expression proteins on series of malignant salivary gland tumors in order to assess their value as a histogenetic marker, which is relevant to tumor grade. 61 MST cases were segregated by proposed histogenesis and immunohistochemistry was performed using antibodies directed against p27 and skp-2. MST of proposed intercalated duct origin (n = 27) showed strong p27 expression (n = 25/27; 93%) in the vast majority of cases and all cases weakly expressed skp-2. MST of proposed excretory duct origin (n = 32) showed strong p27 expression (n = 18/32; 56%) and moderately strong/ strong skp-2 expression (n = 18/32; 56%), respectively, in over half the cases. MST of intercalated duct origin showed evident p27/skp-2 inverse correlation. Differences in p27/skp-2 expression among the MST subtypes correlated with histogenesis and tumor grade, which reinforces the notion that tumor behavior is relevant to the portion of the salivary gland unit from which they arise. MST of proposed intercalated duct origin strongly expressed p27, and not skp-2, unlike MST of proposed excretory duct origin. The immunohistochemical profile of high grade mucoepidermoid carcinoma was distinct from its low/intermediate grade counterparts, suggesting a separate identity. These results may influence future decision making when formulating workable MST categorization schemes. Further studies on a larger series of MST are warranted in order to support the value of our findings.

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

Cited by 132 publications

References 22 publications

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

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

P27/SKP-2 Histochemical Profile is Relevant to Malignant Salivary Gland Tumors (MST) Histogenesis and Tumor Grade

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