Transcription patterns shift dramatically as cells transit from one phase of the cell cycle to another. To better define this transcriptional circuitry, we collected new microarray data across the cell cycle of budding yeast. The combined analysis of these data with three other cell cycle data sets identifies hundreds of new highly periodic transcripts and provides a weighted average peak time for each transcript. Using these data and phylogenetic comparisons of promoter sequences, we have identified a late S-phase-specific promoter element. This element is the binding site for the forkhead protein Hcm1, which is required for its cell cycle-specific activity. Among the cell cycle-regulated genes that contain conserved Hcm1-binding sites, there is a significant enrichment of genes involved in chromosome segregation, spindle dynamics, and budding. This may explain why Hcm1 mutants show 10-fold elevated rates of chromosome loss and require the spindle checkpoint for viability. Hcm1 also induces the M-phase-specific transcription factors FKH1, FKH2, and NDD1, and two cell cycle-specific transcriptional repressors, WHI5 and YHP1. As such, Hcm1 fills a significant gap in our understanding of the transcriptional circuitry that underlies the cell cycle.[Keywords: Hcm1; cell cycle; transcription; genome stability; forkhead; yeast] Supplemental material is available at http://www.genesdev.org.

FOXO3a is a member of the FOXO subfamily of forkhead transcription factors that mediate a variety of cellular processes including apoptosis, proliferation, cell cycle progression, DNA damage and tumorigenesis. It also responds to several cellular stresses such as UV irradiation and oxidative stress. The function of FOXO3a is regulated by a complex network of processes, including post-transcriptional suppression by microRNAs (miRNAs), post-translational modifications (PTMs) and protein–protein interactions. FOXO3a is widely implicated in a variety of diseases, particularly in malignancy of breast, liver, colon, prostate, bladder, and nasopharyngeal cancers. Emerging evidences indicate that FOXO3a acts as a tumor suppressor in cancer. FOXO3a is frequently inactivated in cancer cell lines by mutation of the FOXO3a gene or cytoplasmic sequestration of FOXO3a protein. And its inactivation is associated with the initiation and progression of cancer. In experimental studies, overexpression of FOXO3a inhibits the proliferation, tumorigenic potential, and invasiveness of cancer cells, while silencing of FOXO3a results in marked attenuation in protection against tumorigenesis. The role of FOXO3a in both normal physiology as well as in cancer development have presented a great challenge to formulating an effective therapeutic strategy for cancer. In this review, we summarize the recent findings and overview of the current understanding of the influence of FOXO3a in cancer development and progression.

piRNAs silence transposons to safeguard genome integrity in animals. However, the functions of the many piRNAs that do not map to transposons remain unknown. Here we showed that piRNA targeting in C. elegans can tolerate a few mismatches but prefer perfect pairing at the seed region. The broad targeting capacity of piRNAs underlies the germline silencing of transgenes in C. elegans. Transgenes engineered to avoid piRNA recognition are stably expressed. Interestingly, many endogenous germline-expressed genes also contain predicted piRNA targeting sites, and periodic An/Tn clusters (PATCs) are an intrinsic signal that provides resistance to piRNA silencing. Together, our study revealed the piRNA targeting rules and highlights a unique strategy that C. elegans uses to distinguish endogenous from foreign nucleic acids.

Transcription factor p53 forms a network with associated factors to regulate the cell cycle and apoptosis in response to environmental stresses. However, there is currently no direct genetic evidence to show if or how the p53 pathway functions during organogenesis. Here we present evidence to show that the zebrafish def (digestive-organ expansion factor) gene encodes a novel pan-endoderm-specific factor. A loss-of-function mutation in def confers hypoplastic digestive organs and selectively up-regulates the expression of ⌬113p53, counterpart to a newly identified isoform of p53 produced by an alternative internal promoter in intron 4 of the p53 gene in human. The increased ⌬113p53 expression is limited to within the mutant digestive organs, and this increase selectively induces the expression of p53-responsive genes to trigger the arrest of the cell cycle but not apoptosis, resulting in compromised organ growth in the mutant. Our data demonstrate that, while induction of expression of p53 and/or its isoforms is crucial to suppress abnormal cell growth, ⌬113p53 is tightly regulated by an organ/tissue-specific factor Def, especially during organogenesis, to prevent adverse inhibition of organ/tissue growth.[Keywords: Def (digestive-organ expansion factor); endoderm organogenesis; p53; zebrafish] Supplemental material is available at http://www.genesdev.org.

In Candida albicans, the a1-␣2 complex represses white-opaque switching, as well as mating. Based upon the assumption that the a1-␣2 corepressor complex binds to the gene that regulates white-opaque switching, a chromatin immunoprecipitation-microarray analysis strategy was used to identify 52 genes that bound to the complex. One of these genes, TOS9, exhibited an expression pattern consistent with a "master switch gene." TOS9 was only expressed in opaque cells, and its gene product, Tos9p, localized to the nucleus. Deletion of the gene blocked cells in the white phase, misexpression in the white phase caused stable mass conversion of cells to the opaque state, and misexpression blocked temperature-induced mass conversion from the opaque state to the white state. A model was developed for the regulation of spontaneous switching between the opaque state and the white state that includes stochastic changes of Tos9p levels above and below a threshold that induce changes in the chromatin state of an as-yet-unidentified switching locus. TOS9 has also been referred to as EAP2 and WOR1.White-opaque switching was first observed in a strain of Candida albicans isolated from a fatal bloodstream infection (40). The switch affected the cellular phenotype (1, 41, 42), gene expression (24), and a variety of putative virulence traits (40, 41). It also conferred the capacity to colonize skin (23). An early analysis of clinical strains performed in 1986, however, revealed that only 8% underwent the switch (D. R. Soll, unpublished observation; 44). This observation was enigmatic, since all strains of C. albicans possessed opaque state-specific genes (33). In 2002, Miller and Johnson (31) provided not only an explanation for this enigma but also a role for the whiteopaque transition. They found that while an a/␣ laboratory strain could not switch, MTLa1 and MTL␣2 deletion derivatives of that strain, which were ␣ and a, respectively, could. They demonstrated that switching in the a/␣ strain was repressed by the a1-␣2 complex, the same complex that repressed mating (31). Their results suggested that in order to switch, natural strains, which are predominantly a/␣ (26,30,48), first had to undergo homozygosis to a/a or ␣/␣. Lockhart et al. (30) generalized this observation by demonstrating that while natural a/␣ strains did not undergo white-opaque switching, spontaneously generated MTL-homozygous offspring and natural MTL-homozygous strains did switch. Miller and Johnson (31) further demonstrated that in order to mate, the a and ␣ strains they derived by deleting MTL␣2 and MTLa1, respectively, first had to switch from white to opaque. Lockhart et al. (29) generalized this observation by demonstrating that only natural a/a and ␣/␣ strains that expressed the opaque phenotype could mate. The white-opaque transition, therefore, was an essential and unique step in the C. albicans mating process (3,42,43).In spite of the fundamental role white-opaque switching plays in mating, very little is known about the molecular mechanisms that re...