Our results show the potential importance of miR-221, miR-222, and miR-146b in determining the aggressive properties of PTCs and highlight the need to identify the gene targets of these miRNAs.

We have analyzed t(1;14)(p32;q11) chromosome translocations from two patients with T cell acute lymphocytic leukemia. The chromosome 1 breakpoints of these patients lie within a kilobasepair of each other, and thus define a genetic locus (designated tal) involved in T cell oncogenesis. Moreover, we have identified sequences within tal that potentially encode an amphipathic helix‐loop‐helix motif, a DNA‐binding domain found in a variety of proteins that control cell growth and differentiation. The homology domain of tal is especially related to that of lyl‐1, a gene on chromosome 19 that has also been implicated in T cell oncogenesis. Hence, tal and lyl‐1 encode a distinct family of helix‐loop‐helix proteins involved in the malignant development of lymphocytes.

Hereditary cases of breast and ovarian cancer are often attributed to germ-line mutations of the BRCA1 tumor suppressor gene. Although BRCA1 is involved in diverse cellular processes, its role in the maintenance of genomic integrity may be a key component of its tumor suppression activity. The protein encoded by BRCA1 interacts in vivo with the related BARD1 protein to form a heterodimeric complex that acts as a ubiquitin E3 ligase. Because the enzymatic activity of the BRCA1/BARD1 heterodimer is conserved over a broad phylogenetic range, it is thought to be critical for the central functions of BRCA1. To test this hypothesis, we have generated isogenic clones of embryonic stem cells that do or do not express an enzymatically proficient Brca1 polypeptide. Surprisingly, cells lacking the ubiquitin ligase activity of BRCA1 are viable and do not accumulate spontaneous cytogenetic rearrangements. Gene targeting efficiencies are modestly reduced in these cells, and chromosomal rearrangements arise at elevated rates in response to genotoxic stress. Nonetheless, cells lacking Brca1 enzymatic activity are not hypersensitive to the DNA cross-linking agent mitomycin C. They also form Rad51 focus in response to ionizing radiation and repair chromosome breaks by homologous recombination at wild-type levels. These results indicate that key aspects of BRCA1 function in genome maintenance, including its role in homologydirected repair of double-strand DNA breaks, do not depend on the E3 ligase activity of BRCA1.breast cancer ͉ BRCA1/BARD1 heterodimer ͉ E3 ubiquitin ligase ͉ homologous recombination ͉ DNA double-strand break repair F amilial susceptibility to breast and ovarian cancer is often mediated by germ-line mutations of the BRCA1 tumor suppressor gene (1). Because BRCA1 has been implicated in a broad range of cellular processes, it has an especially important role in the maintenance of genome integrity (2, 3), and studies of genetically engineered mice support a direct role for Brca1 in preserving chromosome stability (4). Indeed, murine ES cells and mouse embryonic fibroblasts (MEFs) with homozygous Brca1 mutations readily accumulate extensive cytogenetic lesions (5, 6). Also, BRCA1 is required for homology-directed repair (HDR) (5, 7, 8), a process that allows for error-free repair of double-stranded DNA breaks (DSBs). In accord with these findings, BRCA1 associates with proteins that mediate DSB repair, such as Rad51, CtIP, and the RAD50/MRE11/NBS1 complex, and is phosphorylated by protein kinases that regulate the cellular response to genotoxic stress, including ATM, ATR, and Chk2/Cds1 (2, 3). As such, a deficiency in DSB repair may contribute to the chromosomal instability characteristic of BRCA1 mutant cells.In vivo, most BRCA1 polypeptides exist as a heterodimeric complex with the related BARD1 protein (9, 10). Both proteins harbor an N-terminal RING domain, an motif required for the enzymatic function of many E3 ubiquitin ligases (11). Although the individual BRCA1 and BARD1 polypeptides display modest E3 ligase...

Almost 30% of patients with T-cell acute lymphoblastic leukemia (T-ALL) bear structural alterations of tal-1, a presumptive proto-oncogene that encodes sequences homologous to the helix-loop-helix (HLH) DNA-binding and dimerization domain. Analysis of the tal-1 gene product reveals that its HLH domain mediates protein-protein interactions with either of the ubiquitously expressed HLH proteins E47 and E12. The resultant tal-1/E47 and tal-1/E12 heterodimers specifically recognize the E-box DNA sequence motif found in eucaryotic transcriptional enhancers. Hence, the tal-l protein shares biochemical properties with other tissue-specific HLH proteins that control cell type determination during myogenesis (e.g., MyoDl) and neurogenesis (e.g., achaete-scute). The data suggest that HLH heterodimers involving tal-) may function in vivo as transcriptional regulatory factors that influence cell type determination during hematopoietic development.

OCT4 and SOX2 are biomarkers of tumorigenesis and early stage OSCC. SOX2 is an independent prognostic factor for OSCC.