p34SEI-1 Inhibits Apoptosis through the Stabilization of the X-Linked Inhibitor of Apoptosis Protein: p34SEI-1 as a Novel Target for Anti–Breast Cancer Strategies

Abstract

The p34SEI-1 protein exerts oncogenic effects via regulation of the cell cycle, which occurs through a direct interaction with cyclin-dependent kinase 4. Such regulation can increase the survival of various types of tumor cells. Here, we show that the antiapoptotic function of p34 SEI-1 increases tumor cell survival by protecting the X-linked inhibitor of apoptosis protein (XIAP) from degradation. Our findings show that p34 inhibits apoptosis. This antiapoptotic effect was eliminated by the suppression of p34 SEI-1 expression. We also determined that direct binding of p34 SEI-1 to the BIR2 domain prevents ubiquitination of XIAP. Interestingly, p34SEI-1 expression is absent or weak in normal tissues but is strongly expressed in tissues obtained from patients with breast cancer. Furthermore, the expression levels of p34 SEI-1 and XIAP seem to be coordinated in human breast cancer cell lines and tumor tissues. Thus, our findings reveal that p34 SEI-1 uses a novel apoptosis-inhibiting mechanism to stabilize XIAP. [Cancer Res 2009;69(3):741-6]

Characterization of a Novel Mechanism of Genomic Instability Involving the SEI1/SET/NM23H1 Pathway in Esophageal Cancers

“…A recent study found that p34 SEI1 could inhibit apoptosis through the stabilization of the X-linked inhibitor of apoptosis protein (13). Our previous study indicated that the oncogenic function of SEI1 was associated with chromosome instability (14).…”

p34SEI-1inhibits ROS-induced cell death through suppression of ASK1

“…Recently, we reported that human breast cancer cells display different sensitivities to various stimuli, including staurosporine, etoposide and cisplatin, depending on their level of p34 SEI-1 protein. 14 On the basis of these results, we tested the p34 SEI-1 dependence of the sensitivities of human colon cancer cells to the cytotoxic stressor H 2 O 2 , which can induce cell death through an increase in intracellular ROS levels.…”

“…Total cell proteins (20 μg) were resolved by sodium dodecylsulfate-PAGE (SDS-PAGE) and transferred to PolyScreen membranes (New England Nuclear, Boston, MA). Membranes were blocked with 5% non-fat dry milk in Tris-buffered saline containing 0.1% Tween-20 (TBS-T), 14 and probed with primary antibodies against p34 (Axxora LLC, San Diego, CA), ASK1, HA, GFP, anti-γ-tubulin (Santa Cruz Biotechnology, Santa Cruz, CA), and/or phospho-ASK1 (Cell Signaling Technology, Beverly, MA). Primary antibodies were detected with horseradish peroxidase-conjugated goat anti-mouse, goat anti-rabbit or donkey anti-goat secondary antibody, as appropriate and proteins were visualized using an enhanced chemiluminescence system (Amersham, Buckinghamshire, UK).…”

p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN

“…20,21 p34 amplification has been observed in various human carcinomas, including pancreatic, 22 lung, 23 and ovarian cancers. 24 p34 was recently reported to be strongly expressed in human breast cancer tissues but was absent or weakly expressed in normal tissues, 25 implying that p34 may be an oncoprotein. We found that p34 (SEI-1) directly interacts with the WW1 domain of NEDD4-1, whereas its close homologs, SEI-2 and SEI-3, do not (data not shown).…”

“…Consistent with this observation, NEDD4-1 potentiates oncogenic Ras-induced cell transformation in a PTENdependent manner, suggesting that aberrant upregulation of NEDD4-1 can suppress PTEN in human cancers. 12,16,25 The finding that NEDD4-1 is an E3 ubiquitin ligase for PTEN raises a very important question: How is NEDD4-1 regulated? Moreover, what factors are intimately involved in the NEDD4-1-mediated degradation of PTEN?…”