Analyses of steroid receptors are important for understanding molecular details of transcriptional control, as well as providing insight as to how an individual transacting factor contributes to cell identity and function. These studies have led to the identification of a superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid. Although animals employ complex and often distinct ways to control their physiology and development, the discovery of receptor-related molecules in a wide range of species suggests that mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.

/pdf/the-steroid-and-thyroid-hormone-receptor-superfamily-1r0qhjfpv5.pdf

The steroid and thyroid hormone receptor superfamily

Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.

https://science.sciencemag.org/content/sci/255/5052/1707.full.pdf

Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system

Inflammation and Alzheimer's disease.

• The initial route of metastases in most patients with melanoma is via the lymphatics to the regional nodes. However, routine lymphadenectomy for patients with clinical stage I melanoma remains controversial because most of these patients do not have nodal metastases, are unlikely to benefit from the operation, and may suffer troublesome postoperative edema of the limbs. A new procedure was developed using vital dyes that permits intraoperative identification of the sentinel lymph node, the lymph node nearest the site of the primary melanoma, on the direct drainage pathway. The most likely site of early metastases, the sentinel node can be removed for immediate intraoperative study to identify clinically occult melanoma cells. We successfully identified the sentinel node(s) in 194 of 237 lymphatic basins and detected metastases in 40 specimens (21%) on examination of routine hematoxylin-eosin—stained slides (12%) or exclusively in immunohistochemically stained preparations (9%). Metastases were present in 47 (18%) of 259 sentinel nodes, while nonsentinel nodes were the sole site of metastasis in only two of 3079 nodes from 194 lymphadenectomy specimens that had an identifiable sentinel node, a false-negative rate of less than 1%. Thus, this technique identifies, with a high degree of accuracy, patients with early stage melanoma who have nodal metastases and are likely to benefit from radical lymphadenectomy. (Arch Surg.1992;127:392-399)

Technical details of intraoperative lymphatic mapping for early stage melanoma.

The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.

/pdf/adipokines-in-inflammation-and-metabolic-disease-2i05swlyav.pdf

Adipokines in inflammation and metabolic disease

TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue

Prostaglandin synthase 2.

AND PERSPECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 282 IDENTIFICATION OF THE FIRST MITOGEN-INDUCIBLE GENES . . . . . . . . .. . . . . . . . . . 286 THE FOS AND JUN GENE FAMILIES. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 287 PRIMARY RESPONSE GENES FROM CELLS TREATED WITH GROWTH FACTORS OR TUMOR PROMOTERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . 290 1. Nuclear Proteins . . . .. . . ......... 291 2. Cytoskeletal and Extracellular Matrix Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 3. Transmembrane Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 295 4. Cytokines ... . . . . . . . . . .. . . . . . . . . . . . . . . . ..... . . .... . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . 295 5. Proteins of Unknown Function . . . ... .. .. . .... . . . . . . . . . . . ... . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . 297 6. Primary Response Genes from a "Late" Library ... ........ .... 298 REGULATION OF PRIMARY RESPONSE GENE EXPRESSION. ......... . . . .. . . . . . . . . . 299 1. c-fos 299 2. c-jun 303 3. JE . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 304 4. egr-lIz;if-268/krox24/NGFI-A/TIS8. 304 5. egr-2/ krox20. ..... ... 304 6. NlO/nur77/NGFI-B/TISI ..... . ...... . . . ... . .... ......... . ...... ......... 305 CELL-SPECIFIC RESTRICTION OF PRIMARY RESPONSE GENES . .. . . . . . . . . . . . . . . . . 305 SECONDARY RESPONSE GENES . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . 306 DO PRIMARY RESPONSE GENES PLAY CAUSAL ROLES I N MODULATING SECONDARY RESPONSE GENES AND CELLULAR PHySIOLOGy? 306 COMMON PRIMARY RESPONSE GENES AND CELLAND LIGANDSPECIFIC RESPONSES . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . ... . . . . . . . . 307 PRIMARY RESPONSE GENE EXPRESSION IN THE NERVOUS SySTEM 309

Primary Response Genes Induced by Growth Factors and Tumor Promoters

Identifying the molecular targets for the beneficial or detrimental effects of small-molecule drugs is an important and currently unmet challenge. We have developed a method, drug affinity responsive target stability (DARTS), which takes advantage of a reduction in the protease susceptibility of the target protein upon drug binding. DARTS is universally applicable because it requires no modification of the drug and is independent of the mechanism of drug action. We demonstrate use of DARTS to identify known small-molecule-protein interactions and to reveal the eukaryotic translation initiation machinery as a molecular target for the longevity-enhancing plant natural product resveratrol. We envisage that DARTS will also be useful in global mapping of protein-metabolite interaction networks and in label-free screening of unlimited varieties of compounds for development as molecular imaging agents.

https://www.pnas.org/content/pnas/106/51/21984.full.pdf

Target identification using drug affinity responsive target stability (DARTS)

Tumor-derived prostaglandin E2 (PGE2) modifies cytokine balance and inhibits host immunity. We hypothesized that a high level of PGE2 production by lung tumor cells is dependent on tumor cyclooxygenase (COX)-2 expression. We found that PGE2 production by A549 non-small cell lung cancer (NSCLC) cells was elevated up to 50-fold in response to interleukin (IL)-1beta. Reversal of IL-1beta-induced PGE2 production in A549 cells was achieved by specific pharmacological or antisense oligonucleotide inhibition of COX-2 activity or expression. In contrast, specific COX-1 inhibition was not effective. Consistent with these findings, IL-1beta induced COX-2 mRNA expression and protein production in A549 cells. Specific inhibition of COX-2 abrogated the capacity of IL-1beta-stimulated A549 cells to induce IL-10 in lymphocytes and macrophages. Furthermore, specific inhibition of A549 COX-2 reversed the tumor-derived PGE2-dependent inhibition of macrophage IL-12 production when whole blood was cultured in tumor supernatants. Our results indicate that lung tumor-derived PGE2 plays a pivotal role in promoting lymphocyte and macrophage IL-10 induction while simultaneously inhibiting macrophage IL-12 production. Immunohistochemistry of human NSCLC tissues obtained from lung cancer resection specimens revealed cytoplasmic staining for COX-2 within tumor cells. This is the first description of functional COX-2 expression by NSCLC cells and the definition of a pathway whereby tumor COX-2 expression and a high level of PGE2 production mediate profound alteration in cytokine balance in the lung cancer microenvironment.

https://cancerres.aacrjournals.org/content/canres/58/6/1208.full.pdf

Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production.

Harvey R. Herschman

Papers

TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue

Prostaglandin synthase 2.

Primary Response Genes Induced by Growth Factors and Tumor Promoters

Target identification using drug affinity responsive target stability (DARTS)

Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production.