Apollon (also known as BRUCE or BIRC6) is a large protein containing baculoviral-IAP-repeat (BIR) and ubiquitin-conjugating enzyme (UBC) domains at the amino- and carboxy termini, respectively. Apollon inhibits apoptosis, but its molecular and physiological function remains unclear. Here we report that Apollon binds to, ubiquitinates and facilitates proteasomal degradation of SMAC and caspase-9, which both contain IAP-binding motifs. Targeted disruption of Apollon in mice caused embryonic and neonatal lethality. Notably, SMAC induced apoptosis in Apollon-deficient cells, but not in Apollon-expressing cells. Furthermore, the IAP-binding motif of SMAC was required to induce apoptosis in Apollon-deficient cells. These results suggest that Apollon has an essential function in preventing SMAC-induced apoptosis.

BackgroundBreast cancer is the most common malignancy and the leading cause of cancer death among women. TIMELESS (TIM), a circadian rhythm regulator, has been recently implicated in the progression of human cancer. However, the role of TIM in the progression of breast cancer has not been well-characterized.MethodsImmunohistochemistry (IHC) staining was used to examine TIM levels in breast cancer specimens. Mammosphere formation analysis and side population analysis were used to examine the effect of TIM on the self-renewal of breast cancer stem cells. A wound healing assay and a Transwell assay were used to determine the role of TIM in breast cancer cell migration and invasion. A soft agar growth assay in vitro and tumorigenicity in vivo were used to determine the role of TIM in tumorigenicity.ResultsTIM levels in both breast cancer cell lines and tissues were significantly upregulated. Patients with high TIM had poorer prognosis than patients with low TIM. Overexpression of TIM dramatically enhanced, while knockdown of TIM suppressed the self-renewal of cancer stem cells (CSCs), cell invasion and migration abilities of breast cancer cells in vitro. Moreover, overexpression of TIM significantly augmented, while knockdown of TIM reduced the tumorigenicity of breast cancer cells in vivo. Mechanism studies revealed that TIM upregulated the expression and the trans-activity of the well-known oncogene MYC. Inhibition of MYC significantly blocked the effects of TIM on CSC population, cell invasion and anchor-independent cell growth.ConclusionTIM plays an important role in promoting breast cancer progression and may represent a novel therapeutic target for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0838-1) contains supplementary material, which is available to authorized users.

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Accumulating evidence suggests that pulmonary expression of a disintegrin and metalloproteinase-33 (ADAM33) serves a key role in the pathogenesis of airway remodeling-related diseases, including asthma. Airway vascular proliferation has been recognized as a key feature of airway remodeling. Our previous study showed that ADAM33 is constitutively expressed in airway vascular smooth muscle cells in patients with asthma, suggesting a potential role of ADAM33 in regulating airway vascular remodeling. Using in vitro human aortic smooth muscle cells (HASMCs) and lentiviral vector carrying short hairpin RNA for ADAM33, the present study aimed to evaluate the influence of ADAM33 silencing on the proliferation and apoptosis of HASMCs and the underlying molecular pathways. Cellular proliferation was observed using the Cell Counting Kit-8 method. Cellular apoptosis was evaluated with Annexin V-PE/7-AAD staining and flow cytometry. Reverse transcription-quantitative PCR and western blotting were used to evaluate the changes in mRNA and protein levels of involved signaling molecules. It was found that silencing of ADAM33 expression in HASMCs significantly inhibited proliferation, but induced the apoptosis of HASMCs. These changes were accompanied by inhibition of the PI3K/AKT/ERK pathway and Bcl-2, but an increase in Bax expression. These results suggested that constitutive expression of ADAM33 may be important to maintain a proliferative phenotype in HASMCs. The influences of ADAM33 on proliferation and apoptosis of HASMCs may involve regulation of PI3K/AKT/ERK and Bax/Bcl-2 pathways. These findings suggested an important role of ADAM33 in airway vascular remodeling and potential therapeutic significance of ADAM33 inhibition in airway remodeling-related diseases.