Exposure of a haploid yeast cell to mating pheromone induces transcription of a set of genes. Induction is mediated through a cis-acting DNA sequence

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In yeast (Saccharomyces cerevisiae), as in other eukaryotes, many positive and negative regulatory factors act in concert to ensure that transcription initiation by RNA polymerase II (pol II)1 is controlled correctly (1). Promoter accessibility is dictated by chromatin structure, which is modulated by chromatinremodeling complexes and histone-modifying enzymes (2). Once a promoter is available, formation of a preinitiation complex begins with binding of TFIID, a complex composed of the TATA box-binding protein (TBP) and several TBP-associated factors (TAFs) (3). TFIID binds to the TATA box sequence present at nearly all yeast promoters (4, 5). Formation of a TFIID-DNA complex creates a platform for assembly of the remaining general transcription factors and pol II (6 -8).Transcriptional activators stimulate transcription initiation via recruitment of the pol II preinitiation complex to a promoter either through direct interaction with TBP, TFIIB, and/or components of the pol II holoenzyme (9, 10) or via intervening "mediator" complexes (11). Considerable evidence highlights the importance of activator recruitment of TBP. For example, by using a TBP derivative with altered DNA binding specificity, it was shown that activator-dependent engagement of TBP at a promoter is rate-limiting for transcription in vivo (12). Also, fusion of TBP to the DNA-binding domains of either LexA or Gal4 allows high level transcription from LexA-or Gal4-binding sites in the absence of any other activator (13-15). Finally, as shown by in vivo cross-linking techniques, promoter occupancy by TBP correlates with transcriptional activity (16,17).Because promoter occupancy by TBP is central to gene activation (18), TBP is also a prime target of transcriptional inhibitors. A conserved heterodimeric repressor, NC2/Dr1/DRAP, binds TBP via a histone-like fold, preventing TBP association with TFIIA and/or TFIIB, thereby repressing transcription (19 -22). S. cerevisiae cells lacking NC2␣ (BUR6/NCB1 gene product) grow very poorly; cells lacking NC2␤ (NCB2 gene product) are inviable (21, 23).Another class of negative transcriptional regulator targeting TBP is the yeast MOT1 gene product. Like NC2, Mot1 is essential for viability and evolutionarily conserved. Mot1 homologs exist in Drosophila (55) and humans (63,64). A recessive temperature-sensitive mutation (mot1-1) elevated transcription of a plasmid-borne reporter gene in the absence of its * This work was supported by a predoctoral fellowship from the Howard Hughes Medical Institute (to J. I. A.), by a University fellowship from the Graduate Division of the University of California, Berkeley, and a predoctoral fellowship from the National Science Foundation (to K. E. H.), by a University of California President's Undergraduate research fellowship (to W. A. P.), by Postdoctoral Fellowship PF-3308 from the American Cancer Society, California Division (to J. L. D.), and by Research Grant GM21841 from the National Institutes of Health and facilities provided by the Berkeley campus Cancer Research L...

IAP (inhibitor of apoptosis) proteins play a central role in many types of cancer, and IAP antagonists are in development as anti-cancer agents. IAP antagonists cause apoptosis in many cells, but they also activate alternative NF-κB signaling through NIK, which regulates osteoclasts. In bone metastasis, a positive feedback loop between tumors and osteoclasts promotes tumor growth and osteolysis. We therefore tested the effect of IAP antagonists on the bone microenvironment for metastasis. In both drug-sensitive and drug-resistant tumors, growth in bone was favored compared to other sites during IAP antagonist treatment. These drugs also caused osteoporosis and increased osteoclastogenesis, mediated by NIK, and enhanced tumor-associated osteolysis. Co-treatment with zoledronic acid, a potent osteoclast inhibitor, reduced IAP antagonist-enhanced tumor growth in bone and osteolysis. Thus, IAP-based cancer treatment may be compromised by osteoporosis and enhanced skeletal metastasis which may be prevented by anti-resorptive agents.