A functional link between Wnt signaling and SKP2-independent p27 turnover in mammary tumors

Miranda-Carboni, Gustavo A.; Krum, Susan A.; Yee, Kathleen M.; Nava, Miguel; Deng, Qiming; Pervin, Shehla; Collado-Hidalgo, Alicia; Galić, Zoran; Zack, Jerome A.; Nakayama, Keiko; Nakayama, Keiichi I.; Lane, Timothy F.

doi:10.1101/gad.1692808

Cited by 67 publications

(86 citation statements)

References 42 publications

(62 reference statements)

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“…Furthermore, we found an inverse relation of mRNA level of the cyclin-dependent kinase inhibitor p27 KIP1 and the amount of cytoplasmatic ßCat (Table II), indicating that the expression of p27(KIP1) could be controlled by Wnt in BTC cells. The p27 protein has been described as a negative Wnt target (39,40). For the mRNA level of Wnt receptors or transcription factors we could not find similar correlations (Tables II and III).…”

Section: Effects Of Wnt Pathway Inhibitioncontrasting

confidence: 35%

Active Wnt signalling is associated with low differentiation and high proliferation in human biliary tract cancer in vitro and in vivo and is sensitive to pharmacological inhibition

Kiesslich

Alinger²,

Wolkersdörfer³

et al. 2009

Int J Oncol

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Abstract. Activation of developmental pathways has been recognized as a key mechanism for tumourigenesis and, hence, might be a valuable target for otherwise difficult to treat tumour entities such as biliary tract cancer (BTC). Therefore, we performed a comprehensive analysis of the Wnt signalling pathway in 9 BTC cell lines on cell blocks, xenograft tumours and on human tissue microarrays by realtime reverse transcription PCR and by immunochemistry. Furthermore, the effects of pharmacological pathway inhibition were investigated. As a result we found a significant positive correlation of Wnt pathway activation with cyclin D1 expression and the proliferation parameters Ki67, cell cycle distribution, and growth kinetics as well as the mesenchymal marker vimentin and an inverse correlation with E-cadherin in BTC cell lines in vitro and in vivo. In human BTC samples loss of membranous ß-catenin, an indicator of active Wnt signalling, correlated with vimentin expression and advanced tumour stage or metastasis, whereas membranous localisation of ß-catenin was associated with the differentiation marker cytokeratin-8/18 and differentiated tumour morphology (ductal or mixed type BTC). In addition, Wnt pathway inhibition by DMAT effectively reduced viability in all cancer cell lines, most effectively in those showing cytoplasmatic ß-catenin localisation, i.e. active Wnt signalling. In summary, activation of the Wnt pathway is associated with high proliferation, dedifferentiation and a solid morphology in human biliary tract cancer cell lines both in vitro and in vivo, and in human BTC tissues. Further investigation of the mechanism(s) of Wnt pathway activation and its inhibition may provide new molecular treatment strategies for biliary tract cancer.

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Section: Effects Of Wnt Pathway Inhibitioncontrasting

confidence: 35%

Active Wnt signalling is associated with low differentiation and high proliferation in human biliary tract cancer in vitro and in vivo and is sensitive to pharmacological inhibition

Kiesslich

Alinger²,

Wolkersdörfer³

et al. 2009

Int J Oncol

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show abstract

“…Previously, Lim et al demonstrated p27 degradative function of Skp2 in low-grade lymphomas but not in aggressive lymphomas (33), which suggests that other factors contribute to deregulation of p27 expression in these tumors. It has been reported that Wnt-induced turnover of p27 was independent from classical SCF Skp2 -mediated degradation in which both Cul4A and Cul4B, components of an alternative E3 ubiquitin ligase, were required for Wnt-induced p27 degradation and S-phase progression (34).…”

Section: Discussionmentioning

confidence: 99%

Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression

Li¹

2010

Int J Oncol

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Abstract. Cullin1 (Cul1) serves as a rigid scaffold in SCF (Skp1/Cullin/Rbx1/F-box protein) complex, the largest family of ubiquitin-protein E3 ligases, and aberrant expression of Cul1 is involved in dysfunction of SCF E3 ligases. Previously, we found that Cul1 expression is increased in early stages of melanoma. In the present study, we further investigated the role of Cul1 in melanoma development. Our results showed that knockdown of Cul1 inhibits melanoma cell growth while overexpression of Cul1 enhances cell proliferation through the control of cell cycle progression. We also found that Cul1 regulates melanoma cell growth and cell cycle progression through degradation of p27 by functional SCF Skp2 complex. This study elucidates the role of Cul1 in melanoma cell proliferation and improves our understanding of increased expression of Cul1 in early stages of melanoma. IntroductionThe cutaneous malignant melanoma derived from epidermal melanocytes is the most serious type of skin cancer. The incidence of melanoma increases steadily in the order of 3-7% per year for fair-skinned Caucasian populations (1). In 1935, the lifetime risk for an American developing invasive melanoma was 1 in 1500. In 2007, this risk is 1 in 63 for invasive melanomas and 1 in 33 if in situ melanomas were included (2-4). With surgical excision, the early diagnosed melanomas are curable, however, up to 20% of patients will develop metastatic tumors due to its high capability of invasion and rapid metastasis to other organs (5,6). The prognosis for patients with advanced melanoma remains poor, and the 5-year survival rate for patients with distant metastases is less than 10% (7).Cancer development is the process by which normal cells are transformed into cancerous cells, which results from aberrant cellular responses to stimuli. This process is regulated by transcription, translation, post-translational modifications and degradation of key regulatory proteins which has a crucial role in maintaining and regulating cellular homeostasis (8,9). The ubiquitin-proteasome system controls the abundance of a number of cellular proteins, including p53, ß-catenin, p21, p27 and cyclins (10-12). Polyubiquitin conjugation of lysine residues in proteins as a result of collaboration with a ubiquitin-activating enzyme (E1), a ubiquitin-conjugation enzyme (E2), and a ubiquitin ligase (E3) is required for selective recognition and degradation by the 26S proteasome (13). Dysfunction of E3 ubiquitin ligases contributes to abnormal cell growth and differentiation (12). The SCF (Skp1/Cullin/Rbx1/F-box protein) complexes are the largest family of Cullin RING ligases (CRL) and ubiquitinate a broad range of proteins (14,15). As a rigid scaffold in SCF complex, Cullin1 (Cul1) plays a key role in SCF complex assembly and aberrant expression of Cul1 results in dysfunction of SCF E3 ligases. Loss of Cul1 results in early embryonic lethality and deregulation of cyclin E (16). Cul1 is modified through the covalent attachment of the ubiquitin-like small molecule Nedd8 and ...

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“…these pathways could be modified by extracellular signaling molecules and operate redundantly in order to regulate cell cycle progression and maintenance of genomic integrity. 50,51 …”

Section: Conditional Inactivation Of Geminin In the Mouse Immune Systemmentioning

confidence: 99%

Life without geminin

et al. 2010

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A functional link between Wnt signaling and SKP2-independent p27 turnover in mammary tumors

Cited by 67 publications

References 42 publications

Active Wnt signalling is associated with low differentiation and high proliferation in human biliary tract cancer in vitro and in vivo and is sensitive to pharmacological inhibition

Active Wnt signalling is associated with low differentiation and high proliferation in human biliary tract cancer in vitro and in vivo and is sensitive to pharmacological inhibition

Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression

Life without geminin

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