Beta-catenin is a key component of the Wnt signaling pathway that functions as a transcriptional co-activator of Wnt target genes. Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and...

Glutamate is the major excitatory neurotransmitter in the mammalian CNS and acts on both ionotropic and metabotropic glutamate receptors (mGluRs). The mGluRs are widely distributed in the CNS and modulate a variety of neuronal processes, including neurotransmitter release and ion channel function. In hippocampus and cortex, mGluR5 is highly expressed and plays an important role in the regulatio...

The Siah (seven in absentia homolog) family of RING-domain proteins are components of ubiquitin ligase complexes, targeting proteins for proteasomal degradation. Siah family members have been reported to function in Ras, estrogen, DNA-damage, and hypoxia response pathways. Although earlier reports implicated Siah proteins as tumor suppressors, recent studies in mouse models have shown that Siah...

Hepatocellular carcinoma (HCC) is a common worldwide malignancy with high morbidity and mortality. Hepatitis B viral (HBV)-encoded X protein (HBx) and natural HBx variants play important roles in HBV-associated HCC development. HBx is an unstable protein that can be degraded in vivo. Our previous study found that the E3 ubiquitin ligase Siah-1 could target HBx for poly-ubiquitylation and protea...

The Drosophila seven in absentia (sina) gene is required for R7 photoreceptor cell formation during Drosophila eye development, where it functions within the Ras/Raf pathway and targets other proteins for degradation via associations with a ubiquitin-conjugating enzyme. Recently, a mammalian sina homologue was reported to be a p53-inducible gene in a myeloid leukemia cell line. To explore the f...

DCC (deleted in colorectal cancer) is postulated to function as transmembrane receptor for the axon and cell guidance factor netrin-1. We report here that the DCC cytoplasmic domain binds to proteins encoded by mammalian homologs of the Drosophila seven in absentia (sina) gene, as well as Drosophila Sina. Sina has a critical role in R7 photoreceptor development and shows upward of 85% amino aci...

The seven in absentia gene (sina) is required for formation of the R7 photoreceptor cell in the developing eye of Drosophila melanogaster. The sina protein contains a putative zinc finger domain and localises to the cell nucleus in Drosophila. We report here the identification of a family of genes in the mouse (designated Siah) with extensive sequence homology to Drosophila sina. The Siah genes...

We have established that the gene AF4, which had long been recognized as disrupted in childhood leukemia, also plays a role in the CNS. Af4 is mutated in the robotic mouse that is characterized by ataxia and Purkinje cell loss. To determine the molecular basis of this mutation, we carried out a yeast two-hybrid screen and show that Af4 binds the E3 ubiquitin ligases Drosophila seven in absentia...

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in a cell death cascade wherein a variety of stimuli activate nitric oxide (NO) synthases with NO nitrosylating GAPDH, conferring on it the ability to bind to Siah, an E3-ubiquitin-ligase, whose nuclear localization signal enables the GAPDH/Siah protein complex to translocate to the nucleus where degradation of Siah targets elicits c...

The translocation and accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the nucleus has closely been associated with cell death induction. However, the mechanism of this process has not been completely understood. The E3 ubiquitin ligase siah-1 (seven in absentia homolog 1) has recently been identified as a potential shuttle protein to transport GAPDH from the cytosol to the n...