Transcript expression of SKP2, a SCF<sup>SKP</sup> component, was elevated in RB1-defective TNBCs, suggesting that in these tumours, SKP2 activity might buffer the effects of RB1 dysfunction.
In accord, knockdown of Skp2 suppressed the ability of MGC803 cells to form tumors and to metastasize to the lungs of mice, and the growth of established tumors, by inhibiting cell proliferation and enhancing cell apoptosis.
Four neuroblastoma xenograft samples derived from cell lines with known N-myc gene copy number were also evaluated, as were 7 samples of non-small cell lung cancer (NSCLC) tumors with known Skp2 gene amplification.
Finally, we describe how the MYC/CDK2/p27/SKP2 axis impacts on tumor development and discuss possible ways to interfere therapeutically with this system to improve cancer treatment.
S phase kinase-associated protein 2 (Skp2) has been shown to be required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb) deficient mice.
The results established a paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation and a mechanism of cell survival by Skp2.
The present results revealed that genistein exerted its tumor suppressor effect at least partially via inhibition of Skp2 and promotion of its downstream targets p21 and p27.
S-phase kinase-associated protein 2 (SKP2) (also known as FBXL1) is often overexpressed in human cancers, and functions as an oncogenic E3 ligase to degrade tumor suppressor gene products.
We also investigated the expression of the gene product in primary GBM by immunohistochemistry, which revealed increased levels of Skp2 in 11 of the 35 tumors examined (31.4%).
Retroviral insertional activation of Fli-1 and Spi-1/PU.1, as well as loss of tumour suppressor genes such as p53 or p45 NFE2 have been shown to be critical for the induction and progression of Friend virus-induced erythroleukemias.
Overexpression of Skp2 and loss of CDKN1B (p27) was strongly associated with aggressive tumor behavior and poor clinical outcome in a variety of cancers, including colorectal cancer.
Skp2 (Fbxl1) directly binds to the tumor suppressor p27 in the context of the SCF<sup>Skp2</sup> E3 ubiquitin ligase to ubiquitylate and target-phosphorylated p27 for proteasomal degradation.
FoxM1 expression was detected in 84.6% of diffuse large B-cell lymphoma tumors and found to be significantly associated with proliferative tumor marker Ki67 (P<0.0001), matrix metalloproteinases-2 (P=0.0008), matrix metalloproteinases-9 (P=0.0002), S-phase kinase associated protein-2 (P<0.0001) and inversely associated with p27 expression (P=0.0215).
High p53-, phospho (p)-Rb-, SKP2-, cyclin D1-, and p-c-myc-positive rates were correlated with HPV-negative tumors, whereas high p16- and p27-positive rates were associated with HPV-positive tumors.
In a xenograft mouse model implanted with PC-3-Pa cells, LJ-2618 (3 or 10 mg/kg) effectively inhibited tumor growth with the enhancement of Skp2 degradation and induction of p27 expression in tumor tissues.
p27(Kip1) (p27) is a tumor suppressor whose stability is controlled by proteasome-mediated degradation, a process directed in part by cyclin-dependent kinase 2 (CDK2)-mediated phosphorylation of p27 at Thr(187) and its subsequent interaction with the Skp1-Cullin-F-box protein/Skp2 (Skp2) ubiquitin ligase.
Using microarray analysis and immunohistochemistry, we determined that higher levels of Skp2 are present more frequently in ER-negative tumors than in ER-positive cases.
Tumor samples were collected to examine the association between the expression of S-phase kinase-associated protein 2 (SKP2) and prognosis in cervical cancer.