p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of the p53 mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we interbred MMTV-v-Ha-ras transgenic mice to either p53-/- knock-out mice or p53R172H/+ knock-in mice to generate mice of three different genotypes: MMTV-ras, MMTV-ras/p53-/-, and MMTV-ras/p53R172H/R172H. Male mice of each of these genotypes were characterized with regard to age of salivary tumor onset and the tumors were characterized with regard to mean growth rates, proliferation fraction, apoptotic levels, and tumor histopathology, as well as responses to doxorubicin treatment. Microarray analysis was also performed to profile gene expression.The MMTV-ras/p53-/- and MMTV-ras/p53R172H/R172H mice display similar properties in age of tumor onset, tumor growth rates, and tumor histopathology, as well as response to doxorubicin. However, a subset of genes show differential expression between the two groups of tumor , and do not appear to be regulated by wild-type p53. At the same time, the MMTV-ras/p53R172H/R172H and MMTV-ras/p53+/+ tumors share similar expression levels of a group of genes that are differentially expressed in the MMTV-ras/p53-/- tumors. Thus, the gain-of-function effects may be caused in part by perturbed regulation of genes not normally regulated by wild-type p53, in addition to imbalances in the regulation of normal p53 target genes.

No description available.

<p>Plant height is an important agronomic trait and a major target for crop improvement. Owing to the ease of detection and measurement of plant stature, as well as its high heritability, several height-related mutants have been reported in maize. The genes underlying a few of those mutants have also been identified, with a majority of them related to the biosynthesis or signaling of two key phytohormones - gibberellins (GAs) and brassinosteroids (BRs). However, most other maize dwarfing mutants, and especially those that result from gain-of-function mutations, remain uncharacterized. The present study was undertaken to characterize a novel dominant dwarfing mutant, named <i>D13</i>. This mutant appeared in the M1 population of the inbred B73 that was generated by mutagenesis with ethyl methanesulfonate (EMS). Like most other maize dwarfing mutants, the reduction in <i>D13</i> height was largely due to the compression of the internodes. However, unlike the GA or BR mutants, <i>D13</i> had no defects in the female or male inflorescences. Further, in contrast to the GA and BR mutants, the mesocotyl elongation during etiolation was not impacted in <i>D13</i>. <i>D13</i> seedlings developed red coloration in two to three lowermost leaves. In addition, <i>D13</i> also showed enhanced tillering when the phenotype was very severe. The size of the shoot apical meristem of <i>D13</i> was reduced slightly, and significant aberrations in the structure of vascular bundles in the mutant were observed. All anatomical and phenotypic features of <i>D13</i> were highly exaggerated in homozygous state, indicating the partially dominant nature of the <i>D13</i> mutation. Interestingly, the heterozygous mutants showed remarkable variation in their phenotype, which was maintained across generations. Moreover, the <i>D13</i> phenotype was found to be sensitive to the genetic background, being completely suppressed in Mo17, Oh7B, enhanced in CML322, P39 and changed to different degrees in others. To identify the genetic defect responsible for the <i>D13</i> mutant phenotype, a map-based cloning approach was used, which identified a single base-pair change from G to A (G2976A) in the coding region of a glutamate receptor gene (Zm00001d015007). The G2976A missense mutation resulted in the replacement of alanine with threonine at the location 670. The replaced alanine is highly conserved in glutamate receptors across all domains of life from cyanobacteria to plants to mammals, suggesting a causal relationship between the G2976A substitution and the <i>D13</i> phenotype. To validate this relationship, a targeted EMS-based mutagenesis approach was used to knock-out (inactivate) the <i>D13</i> mutant allele. A suppressor mutant was found in which the <i>D13</i> mutant phenotype reverted to the normal tall phenotype. The sequence of the revertant allele, designated <i>D13</i>*, revealed that the original <i>D13</i> mutant allele underwent a second G to A mutation (G1520A) to change glycine into aspartic acid at position 473. This intragenic second-site mutation in the <i>D13</i> allele suppressed the function of the <i>D13</i> allele, thereby preventing it from interfering with the function of the wild type allele. To further unveil the genes and underlying mechanisms that enable the <i>D13</i> mutant to confer a dwarf phenotype, transcriptomic and metabolomic analyses of <i>D13</i> mutants were conducted and compared to the wild type sibs. While the omics analysis confirmed that stress responses were upregulated and genes related to shoot system development were downregulated in the mutant, the data did not allow us to pinpoint the underlying mechanisms that connect the <i>D13</i> mutation with its dwarfing phenotype. Furthermore, it remains unclear whether these stress and shoot system-related changes result in the manifestation of <i>D13</i> phenotype, or the dwarf phenotype due to <i>D13</i> mutation activates the stress-related mechanisms. This is the first study that signifies the importance of a glutamate receptor gene in controlling plant height.</p>