Review of gene expression data revealed concordant changes in genes regulating retinoid synthesis, IGF metabolism, TGF-beta signaling and extracellular matrix formation. Gene expression studies provide clues to the relevant pathways of leiomyoma development.

Amplification/overexpression of the human neu protooncogene has been frequently found in human primary breast and ovarian cancers and is correlated with the number of axillary lymph nodes positive for metastasis in breast cancer patients. Identification of the factors controlling transcription of the neu gene is essential for understanding the mechanisms of neu gene regulation and its role in tumorigenicity. The adenovirus early region 1A (E1A) gene products are pleiotropic transcription regulators of viral and cellular genes and have been identified as a viral suppressor gene for metastasis. Here we demonstrate that transcription of neu can be strongly repressed by the ElA gene products. The 13S and 12S products of ElA gene are effective at repressing neu transcription and the transcriptional repression requires the conserved region 2 of the ElA proteins. The target for ElA repression was localized within a 139-base-pair DNA fragment in the upstream region of the neu promoter. In addition, competition experiments suggest that the sequence TGGAATG, within the 139-base-pair fragment, is an important element for the E1A-induced repression. These results indicate that ElA negatively regulates neu gene expression at the transcriptional level by means of a specific DNA element.The neu (also called murine c-erbB-2) oncogene was first identified by transfection studies in which NIH 3T3 cells were transformed with DNA from ethylnitrosourea-induced rat neuro/glioblastomas (1). Structural and functional analysis between the transforming neu oncogene and its normal cellular counterpart, neu protooncogene, revealed that a subtle structural alteration-namely, a single point mutation-is sufficient to convert the neu protooncogene into a transforming neu oncogene (2, 3). The neu gene encodes a 185-kDa transmembrane protein (p185) that is related to, but distinct from, the epidermal growth factor receptor (4). The transforming p185 is associated with an increased tyrosine kinase activity (4-6). Interestingly, a structurally divergent group of oncogenes encoding protein kinases has been shown to induce the metastatic phenotype (7). Evidence linking this kinase oncogene to the induction or progression of human malignancies comes from recent observations that the human homologue of the rat neu oncogene (human gene symbol NGL for neuro/glioblastoma-derived; has been called ERBB2, HER-2, human c-erbB-2, or TKRJ) is amplified/overexpressed in 25-30o of human primary breast cancers and ovarian cancers, notably in breast cancer patients with more than three axillary lymph nodes positive for metastasis (8-10).It has also been noted that some human breast cancer cell lines overexpress human neu mRNA, while the neu gene is not amplified (11). Together, these studies suggest that regulation of the neu gene may play an important role in malignant transformation and metastasis.The primary function of the adenovirus early region 1A (ElA) gene is to activate other adenoviral genes during a permissive viral infection by modifying the ho...

HOX11 encodes a homeodomain protein that is aberrantly expressed in T-cell acute lymphoblastic leukemia as a consequence of the t(10;14) and t(7;10) chromosomal translocations. We previously reported that HOX11 immortalizes murine hematopoietic progenitors and induces pre-Tcell tumors in mice after long latency. It has been demonstrated in a number of studies that HOX11, similar to other homeodomain proteins, binds DNA and transactivates transcription. These findings suggest that translocation-activated HOX11 functions as an oncogenic transcription factor. Here we report that HOX11 represses transcription through both TATAcontaining and TATA-less promoters. Interestingly, transcriptional repression by HOX11 is independent of its DNA binding capability. Moreover, a systematic mutational analysis indicated that repressor activity was separable from immortalizing function, which requires certain residues within the HOX11 homeodomain that make base-specific or phosphatebackbone contacts with DNA. We further IntroductionThe involvement of homeobox genes in hematologic malignancies is becoming increasingly recognized. 1 HOX11 (TCL-3) is a homeobox gene identified on chromosome 10 at the t(10;14)(q24;q11) and t(7;10)(q35;q24) chromosomal translocations associated with pediatric T-cell acute lymphoblastic leukemia (T-ALL). [2][3][4][5] As a result of translocation, the T-cell receptor ␦ or ␤ regulatory region is juxtaposed upstream of the HOX11 coding region, resulting in high-level synthesis of a structurally intact HOX11 homeodomain protein. During murine embryogenesis, Hox11 expression has been detected in the bronchial arches, the hindbrain, and the splenic anlage arising from splanchnic mesoderm. [6][7][8] Because HOX11 is not normally expressed in T cells, dysregulated HOX11 expression as a consequence of aberrant recombinational events during T-cell receptor rearrangement is believed to be an early step in the etiology of this subtype of T-ALL. [2][3][4][5] The transforming potential of HOX11 has been confirmed by both in vitro and in vivo studies. We have previously shown that retroviral vector-mediated expression of HOX11 in primary murine bone marrow (BM) cells gives rise to immortalized progenitor lines at high frequency and promotes T-cell tumorigenesis in mice, 9,10 whereas others have reported that targeted expression of HOX11 in thymocytes of transgenic mice resulted in cell-cycle aberration and progression to malignancy. 11 Several possible mechanisms through which inappropriate HOX11 expression might lead to malignant transformation have been proposed. In particular, HOX11 is believed to function as a transcriptional regulator on the basis of its nuclear localization, the DNA binding activity of its homeodomain, and its ability to transactivate transcription of reporter genes. [12][13][14][15] In support of this view, HOX11 induces the up-regulation of an endogenous gene, Aldh-1, in stably transfected NIH3T3 cells; interestingly, an inverse relationship between Hox11 expression and Aldh-1 expression is...

BackgroundDaily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core.ResultsNearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50–75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues.ConclusionsOverall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0157-x) contains supplementary material, which is available to authorized users.

BRCA1 is the first tumor suppressor gene linked to hereditary breast and ovarian cancers. Its involvement in sporadic breast cancer, however, remains unclear. Recent studies showed that a loss or lowered expression of BRCA1 is not uncommon in nonfamilial breast cancers. In addition, there have been cases of inherited BRCA1-linked breast cancer with as yet unidentified mutation. Misregulation of BRCA1 at the transcription level is a possible mechanism for loss of BRCA1 expression. To understand transcriptional regulation of the BRCA1 gene, we cloned and examined the BRCA1 promoter, by both functional reporter gene analyses and protein-DNA complex formation electrophorectic mobility shift assays. A bi-directional promoter could be located within a 229-base pair (bp) intergenic region between BRCA1 and its neighboring gene, NBR2. Deletion analyses further delineated a minimal 56-bp EcoRIHaeIII fragment, which could drive transcription in the NBR2 gene direction 2-4-fold higher than in the BRCA1 direction in all cell lines tested. Furthermore, transcriptional activity in the BRCA1 direction was undetectable in the muscle cell line C2C12, whereas activity in the NBR2 direction was maintained. These results were consistent with the expression pattern of the respective genes. A specific protein-DNA complex was detected when nuclear extracts from HeLa cells and Caco2, a colon cell line, were incubated with the 56-bp minimal promoter. This protein binding activity was further localized to an 18-bp fragment and might involve a tissuespecific factor, because binding was not detected in the C2C12 cell line. The correlation of the detection of this protein-DNA complex only in those cell lines that expressed the chloramphenicol acetyltransferase reporter gene in the BRCA1 direction suggests a significant positive role of this complex in the transcription of the BRCA1 gene.