SIAH proteins are the human members of an highly conserved family of E3 ubiquitin ligases. Several data suggest that SIAH proteins may have a role in tumor suppression and apoptosis. Previously, we reported that SIAH-1 induces the degradation of Kid (KIF22), a chromokinesin protein implicated in the normal progression of mitosis and meiosis, by the ubiquitin proteasome pathway. In human breast cancer cells stably transfected with SIAH-1, Kid/KIF22 protein level was markedly reduced whereas, the Kid/KIF22 mRNA level was increased. This interaction has been further elucidated through analyzing SIAH and Kid/KIF22 expression in both paired normal and tumor tissues and cell lines. It was observed that SIAH-1 protein is widely expressed in different normal tissues, and in cells lines but showing some differences in western blotting profiles. Immunofluorescence microscopy shows that the intracellular distribution of SIAH-1 and Kid/KIF22 appears to be modified in human tumor tissues compared to normal controls. When mRNA expression of SIAH-1 and Kid/KIF22 was analyzed by real-time PCR in normal and cancer breast tissues from the same patient, a large variation in the number of mRNA copies was detected between the different samples. In most cases, SIAH-1 mRNA is decreased in tumor tissues compared to their normal counterparts. Interestingly, in all breast tumor tissues analyzed, variations in the Kid/KIF22 mRNA levels mirrored those seen with SIAH-1 mRNAs. This concerted variation of SIAH-1 and Kid/KIF22 messengers suggests the existence of an additional level of control than the previously described protein-protein interaction and protein stability regulation. Our observations also underline the need to re-evaluate the results of gene expression obtained by qRT-PCR and relate it to the protein expression and cellular localization when matched normal and tumoral tissues are analyzed.

/pdf/distinct-expression-patterns-of-the-e3-ligase-siah-1-and-its-53xpsl3ncy.pdf

Distinct expression patterns of the E3 ligase SIAH-1 and its partner Kid/KIF22 in normal tissues and in the breast tumoral processes

Ubiquitin pathways regulate the pathogenesis of chronic liver disease.

Solid tumors contain extensive hypoxic areas and it is of considerable importance to decipher the potential role of hypoxia in signaling pathway regulation. In the present study, we examined the impact of hypoxia on β-catenin status and the mechanisms involved. Hypoxia significantly decreased β-catenin protein, but had no effect on glycogen synthase kinase (GSK)-3β or adenomatous polyposis coli (APC) levels. However, hypoxia-induced β-catenin downregulation seemed to require APC but not GSK-3β. Further investigation revealed that hypoxia significantly upregulated Siah-1, the human homolog of Drosophila seven in absentia. In addition, hypoxia augmented the interaction between β-catenin and SIP and Skp1. Silencing of Siah-1, as well as the use of a dominant negative Siah-1 mutant, attenuated these responses to hypoxia and rescued β-catenin transactivation. The Siah-1-mediated degradation of β-catenin during hypoxia may involve p53, but not hypoxia-inducible factor-1, activation. Together, the results suggest that hypoxia downregulates β-catenin by increasing Siah-1 expression in a p53-dependent manner. (Cancer Sci 2011; 102: 1322–1328)

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2011.01950.x

Hypoxia-induced β-catenin downregulation involves p53-dependent activation of Siah-1.

All known human papillomaviruses (HPVs) are exclusively epitheliotropic. Upon entry into populations of stratified epithelial cells, the E6 and E7 oncoproteins encoded by high-risk HPV variants establish a productive infection by manipulating signaling processes in the host environment, leading ultimately to production of infectious particles in the upper epithelial layers. The mechanisms by which E6 and E7 promote cell-cycle progression and viral DNA replication are well established, and involve E6-dependent ubiquitination and degradation of the p53 tumor suppressor, and E7- and cullin 2-dependent ubiquitination and degradation of the retinoblastoma (Rb) tumor suppressor protein. Recent experimental work provides evidence that high-risk HPVs also manipulate the underlying differentiation status of cells by targeting the Wnt pathway to ensure progression of the viral replication cycle. This chapter summarizes the possible cell pathways involved in the activation of Wnt signaling in HPV-positive head and neck cancer.

Human Papillomavirus (HPV)-Positive Head and Neck Cancer and the Wnt Signaling Pathway

SIAH1 facilitates the migration and invasion of gastric cancer cells through promoting the ubiquitination and degradation of RECK

SIAH-1 (seven in absentia homologue-1) is an E3-ubiquitin ligase that facilitates labelling and subsequent proteasomal degradation of different proteins like transcription factors (e.g. c-myb) and coactivators (e.g. beta-catenin). Here we show that SIAH-1 expression is frequently reduced in human hepatocarcinogenesis. However, further reduction of SIAH-1 bioavailability by gene-specific siRNA (RNAinterference) in HCC cell lines resulted in significantly decreased tumor cell viability. Therefore we conclude that distinct SIAH-1 levels mediate pro-tumorigenic effects in HCC cells and that further SIAH-1 inhibition may represent a new therapeutic strategy in the treatment of human hepatocellular carcinoma.

[Reduced expression of the E3-ubiquitin ligase seven in absentia homologue (SIAH)-1 in human hepatocellular carcinoma].

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[Reduced expression of the E3-ubiquitin ligase seven in absentia homologue (SIAH)-1 in human hepatocellular carcinoma].