Biomedical subjects
Publications and source records attributed to Xiaolan Qian.
Anti-phase synchronization (AS) in coupled chaotic oscillators is investigated. The necessary condition for AS is given and the stability of AS is studied. Results are demonstrated with numerical simulations and electronic circuits.
We previously identified loci in the mouse genome that substantially influence the metastatic efficiency of mammary tumors. Here, we present data supporting the idea that the signal transduction molecule, Sipa1, is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Analysis of candidate genes identified a nonsynonymous amino acid polymorphism in Sipa1 that affects the Sipa1 Rap-GAP function. Spontaneous metastasis assays using cells ectopically expressing Sipa1 or cells with knocked-down Sipa1 expression showed that metastatic capacity was correlated with cellular Sipa1 levels. We examined human expression data and found that they were consistent with the idea that Sipa1 concentration has a role in metastasis. Taken together, these data suggest that the Sipa1 polymorphism is one of the genetic polymorphisms underlying the Mtes1 locus. This report is also the first demonstration, to our knowledge, of a constitutional genetic polymorphism affecting tumor metastasis.
The levels of 2-amino-9H-pyrido[2,3-b]indole (AalphaC or 2-amino-alpha-carboline), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC or 2-amino-3-methyl-alpha-carboline), 9H-pyrido[3,4-b]indole (norharman), and 1-methyl-pyrido[3,4-b]indole (harman) have been determined in the mainstream smoke condensate from three reference cigarettes, namely Kentucky reference 1R5F, Kentucky reference 2R4F, and CORESTA CM4. The amino-alpha-carbolines, and norharman and harman (beta-carbolines) can be classified as heterocyclic aromatic amines (HAAs) and are listed as biologically active agents in the mainstream smoke of cigarettes. For the analysis, the mainstream smoke condensate from cigarettes was collected on a filter pad, the analytes were isolated using solid-phase extraction (SPE), and quantified without derivatization on a GC-MS. Total amounts of carbolines found in the condensate increased from ultralight 1R5F to full-flavor CM4 cigarettes. The level of harman was about 250 ng/cigarette for the 1R5F cigarette and about 1025 ng/cigarette for the CM4 cigarette. Norharman was typically three times more abundant than harman. The AalphaC was found at about 10 times lower level compared to harman, and MeAalphaC was about 50 times lower than harman. The use of reference cigarettes can provide a common measure for laboratories to assess carboline amounts among cigarette brands.
E-cadherin is an essential adhesion protein as well as a tumor suppressor that is silenced in many cancers. Its adhesion-dependent regulation of signaling has not been elucidated. We report that E-cadherin can negatively regulate, in an adhesion-dependent manner, the ligand-dependent activation of divergent classes of receptor tyrosine kinases (RTKs), by inhibiting their ligand-dependent activation in association with decreases in receptor mobility and in ligand-binding affinity. E-cadherin did not regulate a constitutively active mutant RTK (Neu*) or the ligand-dependent activation of LPA receptors or muscarinic receptors, which are two classes of G protein-coupled receptors. EGFR regulation by E-cadherin was associated with complex formation between EGFR and E-cadherin that depended on the extracellular domain of E-cadherin but was independent of beta-catenin binding or p120-catenin binding. Transfection of E-cadherin conferred negative RTK regulation to human melanoma and breast cancer lines with downregulated endogenous E-cadherin. Abrogation of E-cadherin regulation may contribute to the frequent ligand-dependent activation of RTK in tumors.
Susceptibility to mouse plasmacytomagenesis is a complex genetic trait controlled by several Pctr loci (Pctr1, Pctr2, etc). Congenic strain analysis narrowed the genetic interval surrounding the Pctr2 locus, and genes identified in the interval were sequenced from susceptible BALB/c and resistant DBA/2 mice. Frap (FKBP12 rapamycin-associated protein, mTOR, RAFT) was the only gene differing in amino acid sequence between alleles that correlated with strain sensitivity to tumor development. The in vitro kinase activity of the BALB/c FRAP allele was lower than the DBA/2 allele; phosphorylation of p53 and PHAS1/4EBP1 (properties of heat and acid stability/eukaryotic initiation factor 4E-binding protein) and autophosphorylation of FRAP were less efficient with the BALB/c allele. FRAP also suppressed transformation of NIH 3T3 cells by ras, with DBA/2 FRAP being more efficient than BALB/c FRAP. Rapamycin, a specific inhibitor of FRAP, did not inhibit growth of plasmacytoma cell lines. These studies identify Frap as a candidate tumor suppressor gene, in contrast to many reports that have focused on its prooncogenic properties. Frap may be similar to Tgfb and E2f in exerting both positive and negative growth-regulatory signals, depending on the timing, pathway, or tumor system involved. The failure of rapamycin to inhibit plasma cell tumor growth suggests that FRAP antagonists may not be appropriate for the treatment of plasma cell tumors. Pctr2 joins Pctr1 in possessing alleles that modify susceptibility to plasmacytomagenesis by encoding differences in efficiency of function (efficiency alleles), rather than all-or-none, gain-of-function, or loss-of-function alleles. By analogy, human cancer may also result from the combined effects of several inefficient alleles.
BALB/c mice are susceptible to the development of pristane-induced plasma cell tumors, and have a rare allelic variant in the coding region of the p16(INK4a) (p16) tumor suppressor gene that produces a protein with impaired activity. We have now found that the BALB/c p16 promoter has an allelic variant that may also compromise p16 activity. Following pristane treatment, BALB/c p16 mRNA levels in B cells were lower than that in DBA/2 or C.D2-Pctr1, a resistant BALB/c congenic strain that harbors DBA/2 chromatin surrounding the p16 locus. Four sequence variants were found between BALB/c and DBA/2 in the p16 promoter region. In reporter assays, the DBA promoter was at least four times more active in driving luciferase expression than the BALB/c promoter. Most of the difference in activity was localized to a single nucleotide deletion in BALB/c. This deletion created a consensus binding site for RREB, a ras-responsive transcriptional element with zinc-finger binding motifs. Transient transfections with RREB confirmed that the p16 promoter can be downregulated by RREB, in a Ras- or Mek-dependent manner, and that the BALB/c promoter is more sensitive than DBA/2 to regulation by RREB. BALB/c mice have both regulatory and coding region defects that may contribute to the impairment of p16 gene function.