The 14-3-3 (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3 is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3 was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3 in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3 has not yet been characterized. Here, we studied the link between 14-3-3 activities and p53 regulation. We found that 14-3-3 interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3 expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3 antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3 facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3 appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3 inhibited oncogene-activated tumorigenicity in a tetracyclineregulated 14-3-3 system. These results defined an important p53 regulatory loop and suggested that 14-3-3 expression can be considered for therapeutic intervention in cancers.

There are approximately 4,800 extant species of mammals that exhibit tremendous morphological, physiological, and developmental diversity. Yet embryonic development has been studied in only a few mammalian species. Among mammals, bats are second only to rodents with regard to species number and habitat range and are the most abundant mammals in undisturbed tropical regions. Bat development, though, remains relatively unstudied. Here, we describe and illustrate a staging series of embryonic development for the short-tailed fruit bat, Carollia perspicillata, based on embryos collected at timed intervals after captive matings. As Carollia can be readily maintained and propagated in captivity and is extremely abundant in the wild, it offers an attractive choice as a chiropteran model organism. This staging system provides a framework for studying Carollia embryogenesis and should prove useful as a guide for embryological studies of other bat species and for comparisons with other orders of mammals. Developmental Dynamics 233:721-738, 2005.

Bat forelimbs are highly specialized for sustained flight, providing a unique model to explore the genetic programs that regulate vertebrate limb diversity. Hoxd9-13 genes are important regulators of stylopodium, zeugopodium, and autopodium development and thus evolutionary changes in their expression profiles and biochemical activities may contribute to divergent limb morphologies in vertebrates. We have isolated the genomic region that includes Hoxd12 and Hoxd13 from Carollia perspicillata, the short-tailed fruit bat. The bat Hoxd13 gene encodes a protein that shares 95% identity with human and mouse HOXD13. The expression pattern of bat Hoxd13 mRNA during limb development was compared with that of mouse. In bat and mouse hindlimbs, the expression patterns of Hoxd13 are relatively similar. However, although the forelimb Hoxd13 expression patterns in both organisms during early limb bud stages are similar, at later stages they diverge; the anterior expression boundary of bat Hoxd13 is posterior-shifted relative to the mouse. These findings, compared with the Hoxd13 expression profiles of other vertebrates, suggest that divergent Hoxd13 expression patterns may contribute to limb morphological variation.

Histone acetylation plays important roles in gene regulation. However, the functions of individual histone acetyltransferases (HATs) in specific developmental transcription programs are not well defined. To define the functions of Gcn5, a prototypical HAT, during mouse development, we have created a series of mutant Gcn5 alleles. Our previous work revealed that deletion of Gcn5 leads to embryonic death soon after gastrulation. Embryos homozygous for point mutations in the catalytic center of Gcn5 survive longer, but die soon after E16.0 and exhibit defects in cranial neural tube closure. Embryos bearing a hypomorphic Gcn5 flox(neo) allele also exhibit neural closure defects and die at or soon after birth. We report here that Gcn5 flox(neo)/flox(neo) and Gcn5 flox(neo)/Δ embryos exhibit anterior homeotic transformations in lower thoracic and lumbar vertebrae. These defects are accompanied by a shift in the anterior expression boundary of Hoxc8 and Hoxc9. These data provide the first evidence that Gcn5 contributes to Hox gene regulation and is required for normal anteroposterior patterning of the mouse skeleton.