Receptor tyrosine kinase signaling regulates different modes of Groucho-dependent control of Dorsal.

Transcriptional control of the Drosophila terminal gap gene huckebein (hkb) depends on Torso (Tor) receptor tyrosine kinase (RTK) signaling and the Rel/NFkappaB homolog Dorsal (DI). DI acts as an intrinsic transcriptional activator in the ventral region of the embryo, but under certain conditions, such as when it is associated with the non-DNA-binding co-repressor Groucho (Gro), it is converted into a repressor. Gro is recruited to the enhancer element in the vicinity of DI by sequence-specific transcription factors such as Dead Ringer (Dri). We examined the interplay between DI, Gro and Dri on the hkb enhancer and show that when acting over a distance, Gro abolishes rather than converts DI activator function. Reducing the distance between DI- and Dri-binding sites, however, switches DI into a Gro-dependent repressor that overrides activation of transcription. Both of the distance-dependent regulatory options of Gro - quenching and silencing of transcription - are inhibited by RTK signaling. These data describe a newly identified mode of function for Gro when acting in concert with DI. RTK signaling provides a way of modulating DI function by interfering either with Gro activity or with Dri-dependent recruitment of Gro to the enhancer.

hairy stripe 7 element mediates activation and repression in response to different domains and levels of Krüppel in the Drosophila embryo.

The Drosophila gap gene Krüppel (Kr) encodes a zinc finger-type transcription factor required for controlling the spatial expression of other segmentation genes during early blastoderm stage. Here we show that two independent and transferable repressor domains of Krüppel act to control expression of the pair-rule gene hairy, and that the minimal cis-acting element of hairy stripe7 (h7) mediates either Krüppel-dependent activation or repression in different regions of the blastoderm embryo. The C-terminal region of Krüppel which encompasses the predominant repressor domain is not essential for activation, but is required to fully suppress h7-mediated transcription in response to high levels of Krüppel activity. This domain contains an interaction motif for dCtBP, a homologue of the human co-repressor CtBP. dCtBP activity is, however, dispensable for Krüppel-mediated repression in the embryo since Krüppel-mediated repression functions in the absence of dCtBP. Possible modes of h7-mediated gene regulation in response to the different domains and levels of Krüppel are discussed.

Activation of posterior pair-rule stripe expression in response to maternal caudal and zygotic knirps activities.

Drosophila pair-rule gene expression, in an array of seven evenly spaced stripes along the anterior-posterior axis of the blastoderm embryo, is controlled by distinct cis-acting stripe elements. In the anterior region, such elements mediate transcriptional activation in response to the maternal concentration gradient of the anterior determinant BICOID and repression by spatially distinct activities of zygotic gap genes. In the posterior region, activation of hairy stripe 6 has been shown to depend on the activity of the gap gene knirps, suggesting that posterior stripe expression is exclusively controlled by zygotic regulators. Here we show that the zygotic activation of hairy stripe 6 expression is preceded by activation in response to maternal caudal activity. Thus, transcriptional activation of posterior stripe expression is likely to be controlled by maternal and zygotic factors as has been observed for anterior stripes. The results suggest that activation and the expression level mediated by the hairy stripe 6-element depend on the number of activator binding sites, likely to involve additive rather than synergistic interactions. We found an identical transacting factor requirement for hairy stripe 6 and 7 expression. The arrangement of the corresponding binding sites for the common factors involved in the control of the two stripes share a high degree of similarity, but some of the factors exert opposite regulatory functions within the two enhancer elements.

Mechanism and Bicoid-dependent control of hairy stripe 7 expression in the posterior region of the Drosophila embryo.

Pair-rule gene hairy (h) expression in seven evenly spaced stripes, along the longitudinal axis of the Drosophila blastoderm embryo, is mediated by a modular array of separate stripe enhancer elements. The minimal enhancer element, which generates reporter gene expression in place of the most posterior h stripe 7 (h7-element), contains a dense array of binding sites for factors providing the trans-acting control of h stripe 7 expression as revealed by genetic analyses. The h7-element mediates position-dependent gene expression by sensing region-specific combinations and concentrations of both the maternal homeodomain transcriptional activators, Caudal and Bicoid, and of transcriptional repressors encoded by locally expressed zygotic gap genes. Caudal and Bicoid, which form complementing concentration gradients along the longitudinal axis of the embryo, function as redundant activators, indicating that the anterior determinant Bicoid is able to activate gene expression in the most posterior region of the embryo. The spatial limits of the h stripe-7 domain are brought about by the local activities of repressors which prevent activation. The results suggest that the gradients of Bicoid and Caudal combine their activities to activate segmentation genes along the entire axis of the embryo.

Laryngeal carcinoma in females.

Between 1950 and 1992, 96 women with squamous cell carcinoma of the larynx were diagnosed and treated in the Department of Otolaryngology and Oncology at Beilinson Medical Center, Israel, and Long Island College Hospital, Brooklyn, New York. Fifty-seven female patients (59%) had glottic carcinoma, 72% of them in stage I. Thirty-eight had supraglottic carcinoma, 68% of them in stages II and III. One patient had stage I subglottic carcinoma. Treatment varied between radiotherapy, surgery, or combined surgery with radiation and/or chemotherapy. The 5-year survival rate was 87%. Although most of the patients had glottic carcinoma in stage I, there was also a high percentage with supraglottic carcinoma, most in advanced stages and with metastases to other regions. The prognosis is not different from that in men. Smoking is an important factor in glottic carcinoma, but not as important as in males.