Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung.

Mitotic error-mediated chromosome instability (CIN) can lead to aneuploidy, chromothripsis, DNA damage and/or whole chromosome gain/loss. CIN may prompt rapid accumulation of mutations and genomic alterations. Thus, CIN can promote carcinogenesis. This CIN process results from a mutation in certain genes or environmental challenge such as smoking, and is highly prevalent in various cancers, including lung cancer. A better understanding of the effects of CIN on carcinogenesis will lead to novel methods for cancer prevention and treatment. Previously Shugoshin-1 (Sgo1(-/+)) mice, a transgenic mouse model of CIN, showed mild proneness to spontaneous lung and liver cancers. In this study, adoptive (T/B-cell based) immunity-deficient RAG1(-/-) Sgo1(-/+) double mutant mice developed lung adenocarcinomas more aggressively than did Sgo1(-/+) or RAG1(-/-) mice, suggesting immune system involvement in CIN-mediated lung carcinogenesis. To identify molecular causes of the lung adenocarcinoma, we used systems biology approach, comparative RNAseq, to RAG1(-/-) and RAG1(-/-) Sgo1(-/+). The comparative RNAseq data and follow-up analyses in the lungs of naive Sgo1(-/+) mice demonstrate that, (i) glutathione is depleted, making the tissue vulnerable to oxidative stress, (ii) spontaneous DNA damage is increased, (iii) oncogenic Wnt signaling is activated, (iv) both major branches of the immune system are weakened through misregulations in signal mediators such as CD80 and calreticulin and (v) the actin cytoskeleton is misregulated. Overall, the results show multi-faceted roles of CIN in lung carcinoma development in Sgo1(-/+) mice. Our model presents various effects of CIN and will help to identify potential targets to prevent CIN-driven carcinogenesis in the lung.

Genes that modulate the sensitivity for anti-microtubule drug-mediated chemotherapy.

Spindle poisons/anti-microtubule drugs are established chemotherapy drugs. These drugs primarily target microtubules and mitotic spindles, activate spindle assembly checkpoint (SAC), resulting in caspase-mediated cell death. However, the terminal phenotypes of drug-treated cells are surprisingly heterogeneous ranging from mitotic catastrophe to apparent senescence, suggesting that input from a variety of signaling pathways influence the cell death process. In recent years, studies revealed several signaling pathways that modulate the efficacy of spindle poisons. In this review, we discuss the genes and pathways whose inhibition or overexpression modulates spindle poison sensitivity. These genes cluster to (i) microtubule, microtubule associating proteins (MAPS) and actin cytoskeleton regulators, (ii) the SAC components, (iii) signaling proteins, (iv) chaperones, (v) cell cycle regulators, (vi) proteasome components, (vii) transcription factors and nuclear receptors, and (viii) apoptotic factors. These gene products would be potential targets for drugs to be combined with spindle poisons. Expression status of these genes would also serve as a prognostic marker for spindle poison-mediated chemotherapy. Understanding signaling pathways involved in drug efficacy will aid to rationally develop synergistic chemotherapy strategy.

Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105.

The region of human chromosome 11p15.5 is linked with Beckwith-Wiedemann syndrome that is associated with susceptibility to Wilms' tumor, rhabdomyosarcoma and hepatoblastoma. TSSC5 (tumor-suppressing subchromosomal transferable fragment cDNA; also known as ORCTL2/IMPT1/BWR1A/SLC22A1L) is located in the region. The expression of TSSC5 and other genes in the region is regulated through paternal imprinting. Mutations and/or reduced expression of TSSC5 have been found in certain tumors. TSSC5 encodes an efflux transporter-like protein with 10 transmembrane domains, whose regulation may affect drug sensitivity, cellular metabolism and growth. Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop. Ectopic expression of RING105 in HeLa cells caused an accumulation of cells during G1 that was not observed with the expression of a form of RING105 in which a residue within the RING finger was mutated to inactivate its ligase activity. UbcH6-RING105 may define a novel ubiquitin-proteasome pathway that targets TSSC5 in mammalian cells.

High dosage expression of a zinc finger protein, Grt1, suppresses a mutant of fission yeast slp1(+), a homolog of CDC20/p55CDC/Fizzy.

Selective proteolysis at and after the onset of anaphase is a key cell cycle event required for sister chromatid separation as well as for exit from mitosis. It requires ubiquitination of substrates by Anaphase Promoting Complex(APC)/Cyclosome. Slp1, a WD-repeat protein, is a putative activator for APC in fission yeast. With another WD- repeat protein, Ste9/Srw1, it is thought to promote the proteolysis in a substrate-specific manner. We report here characterization of a temperature-sensitive (ts) slp1 mutant and its high-dosage suppressor, grt1(+). In cells arrested in metaphase, wild-type Slp1 was preferentially found in a complex with hyperphosphorylated Cut9 (subunit of APC), whereas the ts Slp1 protein, lacking the last 113 amino acids, failed to interact with Cut9. The temperature sensitivity was suppressed by high dosage expression of a zinc finger protein, Grt1. The ts slp1 mutant was unable to maintain the normal level of Grt1 protein. The reduction in the Grt1 level may be a primary defect since high dosage expression of grt1(+) rescues the slp1 mutant. The grt1-suppression had an additive effect to ste9 and wee1-50, both of which partially suppress the ts slp1 mutant. Therefore, grt1(+) would define an independent pathway that facilitates the function of Slp1.