https://escholarship.org/content/qt2cr6b7v8/qt2cr6b7v8.pdf?t=ql2sie

A CBP Integrator Complex Mediates Transcriptional Activation and AP-1 Inhibition by Nuclear Receptors

Steroid hormone receptors: Many Actors in search of a plot

The NFAT family of transcription factors encompasses five proteins evolutionarily related to the Rel/NF B family (Chytil and Verdine 1996; Graef et al. 2001b). The primordial family member is NFAT5, the only NFATrelated protein represented in the Drosophila genome. NFAT5 is identical to TonEBP (tonicity element binding protein), a transcription factor crucial for cellular responses to hypertonic stress (Lopez-Rodriguez et al. 1999; Miyakawa et al. 1999). We focus here on the remaining four NFAT proteins (NFAT1–NFAT4, also known as NFATc1–c4; see Table 1), referring to them collectively as NFAT. The distinguishing feature of NFAT is its regulation by Ca and the Ca/calmodulin-dependent serine phosphatase calcineurin. NFAT proteins are phosphorylated and reside in the cytoplasm in resting cells; upon stimulation, they are dephosphorylated by calcineurin, translocate to the nucleus, and become transcriptionally active, thus providing a direct link between intracellular Ca signaling and gene expression. NFAT activity is further modulated by additional inputs from diverse signaling pathways, which affect NFAT kinases and nuclear partner proteins. In the first part of this review, we describe the influence of these multiple inputs on the nuclear–cytoplasmic distribution and transcriptional function of NFAT. Recent structural data emphasize the remarkable versatility of NFAT binding to DNA. At composite NFAT:AP-1 elements found in the regulatory regions of many target genes, NFAT proteins bind cooperatively with an unrelated transcription factor, AP-1 (Fos–Jun; Chen et al. 1998). At DNA elements that resemble NF B sites, NFAT proteins bind DNA as dimers (Giffin et al. 2003; Jin et al. 2003). In the second section of this review, we describe these two modes of DNA binding by NFAT. NFAT also acts synergistically with transcription factors other than Fos and Jun, but the structural basis for synergy remains unknown. Drawing on published structures, we discuss the potential cooperation of NFAT with other classes of DNA-binding proteins. It is clear that NFAT activates transcription of a large number of genes during an effective immune response (Rao et al. 1997; Kiani et al. 2000; Serfling et al. 2000; Macian et al. 2001). In the third part of this review, we present information obtained from these studies, highlighting experimental and bioinformatics approaches to identifying NFAT target genes. We discuss the finding that NFAT and NFAT–Fos–Jun complexes activate distinct subsets of target genes in lymphocytes (Macian et al. 2002). We also describe a novel aspect of gene regulation by NFAT, in which this transcription factor participates in an early phase of chromatin remodeling that occurs at specific genetic loci in differentiating T cells (Avni et al. 2002). There is evidence that NFAT regulates cell differentiation programs in cell types other than immune cells (Crabtree and Olson 2002; Horsley and Pavlath 2002; Graef et al. 2003; Hill-Eubanks et al. 2003). In the last section of this review, we select three differentiation programs—fiber-type specification in differentiated skeletal muscle, cardiac valve development, and osteoclast differentiation—for detailed consideration. We evaluate the evidence for NFAT involvement, point out novel cellular and molecular mechanisms that might regulate this familiar transcription factor, and discuss how NFAT exerts its biological effects. Because the phenotypes of NFAT knockout mice have been reviewed elsewhere (Crabtree and Olson 2002; Horsley and Pavlath 2002), we refer to them only as necessary to illustrate specific points.

/pdf/transcriptional-regulation-by-calcium-calcineurin-and-nfat-4i9eqctq32.pdf

Transcriptional regulation by calcium, calcineurin, and NFAT

American Bankruptcy Institute Law Review 17 Am. Bankr. Inst. L. Rev., No. 1, Spring, 2009. Boston College Law Review 50 B.C. L. Rev., No. 3, May, 2009. Boston University Public Interest Law Journal 18 B.U. Pub. Int. L.J., No. 2, Spring, 2009. Cardozo Journal of Conflict Resolution 10 Cardozo J. Conflict Resol., No. 2, Spring, 2009. Cardozo Public Law, Policy, & Ethics Journal 7 Cardozo Pub. L. Pol’y & Ethics J., No. 3, Summer, 2009. Chicago Journal of International Law 10 Chi. J. Int’l L., No. 1, Summer, 2009. Colorado Journal of International Environmental Law and Policy 20 Colo. J. Int’l Envtl. L. & Pol’y, No. 2, Winter, 2009. Columbia Journal of Law & the Arts 32 Colum. J.L. & Arts, No. 3, Spring, 2009. Connecticut Public Interest Law Journal 8 Conn. Pub. Int. L.J., No. 2, Spring-Summer, 2009. Cornell Journal of Law and Public Policy 18 Cornell J.L. & Pub. Pol’y, No. 1, Fall, 2008. Cornell Law Review 94 Cornell L. Rev., No. 5, July, 2009. Creighton Law Review 42 Creighton L. Rev., No. 3, April, 2009. Criminal Law Forum 20 Crim. L. Forum, Nos. 2-3, Pp. 173-394, 2009. Delaware Journal of Corporate Law 34 Del. J. Corp. L., No. 2, Pp. 433-754, 2009. Environmental Law Reporter News & Analysis 39 Envtl. L. Rep. News & Analysis, No. 7, July, 2009. European Journal of International Law 20 Eur. J. Int’l L., No. 2, April, 2009. Family Law Quarterly 43 Fam. L.Q., No. 1, Spring, 2009. Georgetown Journal of International Law 40 Geo. J. Int’l L., No. 3, Spring, 2009. Georgetown Journal of Legal Ethics 22 Geo. J. Legal Ethics, No. 2, Spring, 2009. Golden Gate University Law Review 39 Golden Gate U. L. Rev., No. 2, Winter, 2009. Harvard Environmental Law Review 33 Harv. Envtl. L. Rev., No. 2, Pp. 297-608, 2009. International Review of Law and Economics 29 Int’l Rev. L. & Econ., No. 1, March, 2009. Journal of Environmental Law and Litigation 24 J. Envtl. L. & Litig., No. 1, Pp. 1-201, 2009. Journal of Legislation 34 J. Legis., No. 1, Pp. 1-98, 2008. Journal of Technology Law & Policy 14 J. Tech. L. & Pol’y, No. 1, June, 2009. Labor Lawyer 24 Lab. Law., No. 3, Winter/Spring, 2009. Michigan Journal of International Law 30 Mich. J. Int’l L., No. 3, Spring, 2009. New Criminal Law Review 12 New Crim. L. Rev., No. 2, Spring, 2009. Northern Kentucky Law Review 36 N. Ky. L. Rev., No. 4, Pp. 445-654, 2009. Ohio Northern University Law Review 35 Ohio N.U. L. Rev., No. 2, Pp. 445-886, 2009. Pace Law Review 29 Pace L. Rev., No. 3, Spring, 2009. Quinnipiac Health Law Journal 12 Quinnipiac Health L.J., No. 2, Pp. 209-332, 2008-2009. Real Property, Trust and Estate Law Journal 44 Real Prop. Tr. & Est. L.J., No. 1, Spring, 2009. Rutgers Race and the Law Review 10 Rutgers Race & L. Rev., No. 2, Pp. 441-629, 2009. San Diego Law Review 46 San Diego L. Rev., No. 2, Spring, 2009. Seton Hall Law Review 39 Seton Hall L. Rev., No. 3, Pp. 725-1102, 2009. Southern California Interdisciplinary Law Journal 18 S. Cal. Interdisc. L.J., No. 3, Spring, 2009. Stanford Environmental Law Journal 28 Stan. Envtl. L.J., No. 3, July, 2009. Tulsa Law Review 44 Tulsa L. Rev., No. 2, Winter, 2008. UMKC Law Review 77 UMKC L. Rev., No. 4, Summer, 2009. Washburn Law Journal 48 Washburn L.J., No. 3, Spring, 2009. Washington University Global Studies Law Review 8 Wash. U. Global Stud. L. Rev., No. 3, Pp.451-617, 2009. Washington University Journal of Law & Policy 29 Wash. U. J.L. & Pol’y, Pp. 1-401, 2009. Washington University Law Review 86 Wash. U. L. Rev., No. 6, Pp. 1273-1521, 2009. William Mitchell Law Review 35 Wm. Mitchell L. Rev., No. 4, Pp. 1235-1609, 2009. Yale Journal of International Law 34 Yale J. Int’l L., No. 2, Summer, 2009. Yale Journal on Regulation 26 Yale J. on Reg., No. 2, Summer, 2009.

/pdf/current-index-to-legal-periodicals-8re353ze53.pdf

Current index to legal periodicals

http://mammoth.bcm.tmc.edu/papers/lichtarge-2.1996.pdf

An evolutionary trace method defines binding surfaces common to protein families

Selective gene transcription is mediated in part by regulatory proteins that bind to DNA response elements These regulatory proteins receive global information from signal-transduction events But transcriptional regulators may also be modified in an allosteric manner by response elements themselves to generate the pattern of regulation that is appropriate to an individual gene

Allosteric effects of DNA on transcriptional regulators.

We have isolated two independent mutations in the DNA-binding domain of the rat glucocorticoid receptor, P493R and S459A, that implicate DNA binding in the control of attached transcriptional activation domains, either that of the receptor itself or of VP16. The mutants are capable of activating transcription normally, but unlike wild-type receptors, they interfere with particular transcriptional activators in yeast and mammalian cells, and inhibit growth when overexpressed in yeast. The mutant residues reside at positions within the three-dimensional structure of the receptor that could, in principle, transduce structural changes from the DNA-binding surface of the receptor to other functional domains. These findings, together with the salt dependence of specific and nonspecific DNA binding by these receptors, suggest that specific DNA acts as an allosteric effector that directs the functional interaction of the receptor with targets of transcriptional activation and that the P493R and S459A mutants mimic the allosteric effect of specific DNA, allowing the receptor to interact with regulatory targets even in the absence of specific DNA binding.

/pdf/influence-of-a-steroid-receptor-dna-binding-domain-on-1kli23z5ip.pdf

Influence of a steroid receptor DNA-binding domain on transcriptional regulatory functions.

Mutations in the glucocorticoid receptor DNA-binding domain mimic an allosteric effect of DNA

Modern American patent law is characterized by two grand themes, both of which were first sounded in the formative years of patent law but have assumed center stage today. The first has been the condensation of the invention and the inventor's legal rights around the claim, a highly formal and abstract collection of properties defining the boundaries of the patent's reach. The second has been the drive to reduce patent law to a small set of formal principles, from which the essential doctrines of patent law may be logically derived. This Article argues that those two themes are fundamentally incompatible, and that one cannot succeed but at the expense of the other. In particular, a coherent doctrine of claim scope cannot be formulated in terms of patent law's enablement doctrine without abandoning the basic tenets of the claim system. If we are to preserve the modern claim system, we must invoke the doctrine of written description, a remnant of the pre-claim era whose nature and continued existence is hotly contested today. This Article contends that the true function of the written description doctrine is to serve as a doctrine of definition. Once this function is recognized, the essential role of written description in modern patent law becomes clear.

/pdf/the-formal-structure-of-patent-law-and-the-limits-of-tmdu1c4tdd.pdf

The Formal Structure of Patent Law and the Limits of Enablement

The law of patent claim interpretation articulated by the United States Court of Appeals for the Federal Circuit is commonly supposed to be markedly indeterminate, and to be responsible for a lack of certainty and predictability in patent infringement litigation. But there has been no attempt to measure objectively the indeterminacy associated with patent claim interpretation, or, for that matter, of any other field of law. This Article shows that under appropriate conditions the indeterminacy of a legal regime may be measured empirically by the frequency of judicial dissents. Application of this method to the Federal Circuit's jurisprudence demonstrates that while patent litigation as a whole is less determinate than other bodies of law overseen by the Federal Circuit, there is little or no evidence that claim interpretation is any more or less indeterminate than other aspects of patent law over time. Nor is the law of claim interpretation any less determinate than that of another interpretive regime, contract interpretation. When the indeterminacy of patent law is taken into account, the district courts perform as well, or better, than the specialized tribunals reviewed by the Federal Circuit. These findings call into question the notion that specialized trial courts are necessary to bring certainty or predictability to patent infringement litigation.

/pdf/the-measure-of-the-doubt-dissent-indeterminacy-and-slhd3xo1zr.pdf

Jeffrey A. Lefstin

Papers

Allosteric effects of DNA on transcriptional regulators.

Influence of a steroid receptor DNA-binding domain on transcriptional regulatory functions.

Mutations in the glucocorticoid receptor DNA-binding domain mimic an allosteric effect of DNA

The Formal Structure of Patent Law and the Limits of Enablement

The Measure of the Doubt: Dissent, Indeterminacy, and Interpretation at the Federal Circuit