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Steroid Receptors, Transcription Factors, and Gene Expression Aacrspecial Conferencein Cancer Research1

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Steroid Receptors, Transcription Factors, and Gene Expression Aacrspecial Conferencein Cancer Research1 [CANCER RESEARCH 50, 6430-6435, October 1. 1990] Meeting Report Steroid Receptors, Transcription Factors, and Gene Expression AACRSpecial Conferencein Cancer Research1 Understanding the mechanisms controlling normal and ma estrogen receptor-positive patients. These proteins, localized lignant cellular physiology has evolved into studies on the basic primarily in the cytoplasm of female reproductive tissue and molecular biology and biochemistry of receptors, transcription some breast cells, are regulated by estrogen and environmental factors, and the regulation of gene expression. Independent stress. functional domains exist within receptors and many other tran Another example of alteration in cell function involves the scription factors for DNA binding, ligand binding, trans-acti regulatory hierarchy controlling yeast type (I. Herskowitz, Uni vation, and interaction with other transcriptional regulatory versity of California, San Francisco, CA). This is regulated by factors, including other receptors. While some receptors are alíeleswitching and the subsequent expression of both DNA ligand activated, others are ligand independent. Active receptors binding proteins for conserved sequence elements and a vast bind specific response elements in target genes and interact array of transcription factors. The cell cycle of Ustilago mayáis (corn smut) is determined by a dimorphism between 2 forms. directly with the diverse array of factors involved in formation The haploid form is yeast-like, nonpathogenic, unicellular, and and function of active transcription complexes. Receptors can stimulate or inhibit gene expression transcriptionally and post- free living. The dikaryotic form is filamentous, pathogenic, and transcriptionally by direct and indirect mechanisms. Cell-, tis mull ¡cellularand requires corn for growth. This dimorphism is sue-, species-, and developmental-specific controls exert equally governed by 2 loci, a and A, the incompatibility or mating type loci. Development of the pathogenic dikaryon is initiated after profound influences. Finally, steroid and polypeptide hor cell fusion of 2 haploids that differ at both loci. mones, growth factors, signal transduction systems, transcrip The 2 loci are quite different. The a locus has only 2 alíeles tion factors, and oncogenes are all involved in maintaining the and different alíelesare necessary for development of the patho tenuous balance required for proper cell function. It is the genic form. In contrast, there are estimated to be 25 naturally disruption of this balance that leads to malignancies such as occurring alíelesof the b locus. Since any combination of breast cancer. Thus, it is an implicit assumption that under different b alíelestriggers the pathogenic program, this locus standing the intricate molecular and biochemical events con governs the switch between programs. trolling cellular functions will allow better treatment and diag The b locus contains an ORF2 of 410 amino acids that is nosis of cancer. responsible for b activity. Comparisons of the ORFs of 4 different b alíelesshowed that each contains a varible domain Control of Cell Function in the NH2-terminal 110 amino acids (40% identity). The rest The transformation or switch from normal to tumor cells of the ORF is highly conserved (93% identity) and contains a that results in breast cancer can arise from a variety of altera motif related to the homeodomain involved in DNA binding. tions in normal cell function. Several molecular factors have Thus, it was proposed that the b alíelescode for polypeptides been studied for their predictive value in the clinical outcome the association of which yields a regulatory protein that governs of treatments for axillary node-negative breast cancer. Nuclear the developmental program and pathogenicity of this organism. Yeast mating-type interconversion, the process by which grade II or III (poor), low or absent estrogen binding activity, haploid cells switch between a and a cell types, is initiated by a tumor size greater than 2 cm, increased number of positive site-specific endonuclease encoded by the HO gene. Expression lymph nodes, increased number of diploid cells, increased cells of this gene is restricted to mother cells during a short period in S phase measured by flow cytometry, increased cathepsin D in late G, after the cell has committed itself to another mitotic (possibly involved in tumor invasiveness), and expression of the cell cycle. HO is repressed in diploid (a/a) cells. Thus, HO oncogene HER-2/neu are characteristics of transformation but transcription is sensitive to whether a cell is haploid or diploid, are of limited, or no, predictive value alone (W. L. McGuire, whether it is a mother or daughter, and its stage in the cell University of Texas Health Science Center, San Antonio, TX). cycle. However, it was postulated that combinatorial evaluations of HO expression is regulated by the 1400-base pair upstream these parameters may substantially increase the power of as of the start of transcription, termed URS1, which contains sessing clinical outcome. Finally, prognosis is poor if levels of determinants of mother-cell specificity. URS2 contains a re the heat shock proteins HSP27/282 are increased, even in peated sequence motif (consensus PuNNPyCACGAAAA) re sponsible for cell cycle-regulated HO expression. These re Received 6/19/90; accepted 6/27/90. ' This meeting, sponsored by the American Association for Cancer Research, peated elements are referred to as cell cycle boxes. Cell cycle Inc.. took place February 10-13, 1990, in San Diego, CA. The General Motors box factor binds within URS2 and requires the SW1 and SW6 Cancer Research Foundation provided a generous grant for the conference. gene products. The cell cycle box factor-URS2 complex is Members of the Program Committee were: Bert W. O'Malley, Baylor College of regulated by signals from yeast cell cycle regulators, including Medicine, Houston, TX; Ronald M. Evans, The Salk Institute, La Jolla, CA; and Marc E. Lippman, Vincent T. Lombardi Cancer Center, Washington, DC. negative regulation by the SIN\ gene product. On the other 2The abbreviations used are: HSP, heat shock protein; ORF, open reading hand, SW\, -2, and -3 act as activators of URS 1 and antagonize frame; URS, upstream regulatory sequence; RAR, retinole acid receptor; 8-Br- the action of SIN1. cAMP. 8-bromo-cyclic AMP; PR, progesterone receptor; GR, glucocorticoid receptor; UAS1, upstream activating sequence 1; ATF, activating transcription Mechanism of Action in the Steroid/Thyroid Hormone Receptor factor; TRE, thyroid hormone response elements; TR, thyroid hormone; LTR, long terminal repeat; TGF, transforming growth factor; CRE, cAMP response Superfamily elements; CREB, cAMP response element-binding protein; ER, estrogen receptor; TFIID, transcription factor HD; pol II, polymerase II; CTD, COOH-terminal The steroid/thyroid hormone receptor superfamily also in domain. cludes receptors for vitamin D and retinoids. These proteins 6430 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1990 American Association for Cancer Research. MEETING REPORT are homologous in 3 regions. The central portion contains a mobilities of the complexes, suggesting that TR causes bending highly conserved DNA binding domain that consists of 2 zinc of the DNA. fingers. The COOH-terminal domain contains 2 additional Glucocorticoid Receptors. Although simplified models of conserved regions involved in ligand binding. transcription, which overlook the influence of chromatin struc Orphan Receptors. Screening for genes containing regions ture, have been very important, studies on this additional level homologous to the DNA binding domain led to the isolation of complexity are essential to understand regulation of gene of several new genes coding for members of this superfamily. transcription in vivo. LTR of mouse mammary tumor virus These are called orphan receptors, since the ligands are un contains 4 repeats, tandem or imperfect palindromes, which known. Examples include hRXR-a; ERRI and -2; NGF1-B; bind glucocorticoid and progesterone receptors, as well as NF- hTR2; EAR 1, 2, and 3; and the Drosophila kni, knrl, and E75. 1. The LTR contains precisely phased nucleosomes covering hRXR-a has low homology with the RAR, TR, or GR but the hormone-responsive element from —250to —60nucleotides. possesses significant homology with a Drosophila receptor (R. Hydroxyl radical footprinting shows a precise, sinusoidal ac M. Evans, Salk Institute, La Jolla, CA). hRXR-a has similar cessibility to cleavage. Footprinting data confirm the prediction affinity for natural retinoids such as RAR, but unlike RAR that the 2 upstream and 1 downstream glucocorticoid response binds poorly to synthetic retinoids. The low homology between element-progesterone response element sites would be inacces RAR and hRXR-a suggests that they are not evolutionarily sible due to nucleosome structure (M. Beato, Institute for related and therefore that the latter is unlikely to be a member Molecular Biology and Cancer Research, Marburg, West Ger of the RAR gene subfamily. many). Furthermore, exonuclease III digestion of LTR-nucleo- Retinoic Acid Receptors. The response elements for retinoic some complexes reveals a pattern of "breathing" of the com acid and vitamin D receptors in the osteocalcin gene promoter plexes with a regular pattern of interaction. PR and GR can also contain an overlapping AP-1 site (R. M. Evans). This site displace nucleosomes and alter these
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