Ubiquilin1 represses migration and epithelial-to-mesenchymal transition of human non-small cell lung cancer cells.

Ubiquilin1 (UBQLN1) is a ubiquitin-like domain and a ubiquitin-associated domain containing protein that has been reported to be involved in shuttling proteins to the proteasome, especially during endoplasmic reticulum-associated protein degradation. Thus, UBQLN1 function has been shown to be critical for combating a number of neurological disorders caused by protein aggregation, such as amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. A role for UBQLN1 in regulating processes involved in tumorigenesis has not been demonstrated. Herein, we show that loss of UBQLN1 causes increased cell migration and invasion, actin cytoskeleton reorganization and induction of epithelial-to-mesenchymal transition (EMT). Loss of UBQLN1 results in a significant decrease in the expression of epithelial markers including E-cadherin and claudin1, whereas expression of mesenchymal markers including Vimentin, Snail and ZEB1 are significantly elevated. Interestingly, we found that ZEB1 is required for induction of mesenchymal-like properties following loss of UBQLN1 and ZEB1 is capable of repressing expression of UBQLN1, suggesting a physiological, reciprocal regulation of EMT by UBQLN1 and ZEB1. Further, we find evidence for a role for UBQLN2 in also regulating EMT and cell migration. These observations have potential clinical relevance because the UBQLN1 gene is lost and underexpressed in a large percentage of human cancer cell lines, and primary human lung cancer samples and recurrent mutations in all five UBQLN family members have been identified in human lung cancers. Taken together, our results suggest for the first time a role for UBQLN family members in cancer biology.

MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family.

Signals that control the fine balance between cell death and cell survival are altered during tumorigenesis. Understanding the mechanisms by which this balance is perturbed, leading to excessive cell survival, is important for designing effective therapies. Proteins belonging to the B-cell lymphoma (BCL) family are known to regulate death responses to apoptotic signals, especially those originating within cells. A subset of BCL family members capable of inhibiting cell death is known to contribute to tumorigenesis; however, it is not known whether all six antiapoptotic BCL family members play a causal role in tumor development. Using a mouse model of MYC-driven leukemia, we showed that, in addition to the well characterized BCL2 and BCLxl (BCL2L1), the other four family members -- BCLw (BCL2L2), BCLb (BCL2L10), BFL1 (BCL2A1) and MCL1 -- also cooperate with MYC to accelerate leukemogenesis. In addition, high levels of each family member are found in either solid human tumors or cell lines derived from human leukemias or lymphomas.

Expression of JAGGED1 in T-lymphocytes results in thymic involution by inducing apoptosis of thymic stromal epithelial cells.

Proper development of the thymus and differentiation of T-lymphocytes requires cell-cell interactions between the developing T-lymphocytes and the thymic epithelia. The Delta/Serrate/Lag-2 (DSL)/Notch signal-transduction pathway is known to govern cell fate decisions required for proper development through direct cell-cell interactions. The functional consequences of specific DSL/Notch interactions during the development of a complex organ, such as the thymus, have not been thoroughly elucidated, however. In order to examine the role of DSL proteins during thymus development and T-lymphocyte differentiation, we targeted expression of JAGGED1 in T-lymphocyte progenitors via the control of the proximal lck promoter. Here, we report that expression of JAGGED1 in T cells causes premature involution of the thymus by directing thymic epithelial cells to undergo an apoptotic program. Adoptive transfer of JAGGED1 transgenic bone marrow into non-transgenic mice revealed that JAGGED1 expression on T cells does not alter T-cell differentiation, but is directly responsible for involution of the thymus. We propose that the phenotype of the lck-JAGGED1 transgenic mice is a direct result of specific DSL/Notch interactions and improper cell-to-cell signaling.