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P Herrlich

Publications and source records attributed to P Herrlich.

At least 127 records · Page 7Linked to original sources
PubMed1992

Interference of pathway specific transcription factors.

A mechanism for reversibility of cellular decisions, e.g., proliferation or differentiation, is mediated by direct interference of pathway-specific transcription factors. Due to the relative activity of the transcription factors, genetic programs are reversibly switched on and off. In the case of the transcription factors AP-1 and the family of steroid hormone receptors (including retinoic acid receptor, thyroid hormone and vitamin D receptors) two different mechanisms account for negative interference. In one case overlapping DNA binding sites are suggestive of mutually exclusive binding of transcription factors to account for repression. In the other case, a DNA bound transcription factor is attacked by another one via protein-protein interaction, without the need of the latter factor binding to DNA. Although it is not excluded, that also in the case of overlapping DNA binding elements protein-protein interaction might in fact be responsible for repression instead of substitution, the two situations can be clearly distinguished by specific mutants in the glucocorticoid receptor and in Jun and Fos. For the interaction mechanism, we favor the interpretation that the binding of one transcription factor to another one interferes with transactivation directly without influence on DNA binding. The fact that at least two different mechanisms are established to guarantee effective interference, demonstrates how important this type of transcription factor crosstalk is.

Amino Acid Sequence↗
PubMed1992

Interference between pathway-specific transcription factors: glucocorticoids antagonize phorbol ester-induced AP-1 activity without altering AP-1 site occupation in vivo.

Phorbol esters stimulate and glucocorticoid hormones down-regulate a variety of promoters such as that of the collagenase gene through the transcription factor AP-1 (Fos/Jun). We now show by genomic footprinting of the collagenase promoter that phorbol ester treatment of cells results in the binding of AP-1 to its cognate DNA binding site in vivo. The DNA-protein contacts obtained in living cells are also found in vitro using cloned DNA and purified AP-1. Although in vitro synthesized glucocorticoid receptor can disturb the DNA binding of Jun homodimers, it does not interfere with the binding of Fos-Jun heterodimers or of purified AP-1 in vitro. Consistently, fully inhibitory doses of glucocorticoid hormone cause no change in apparent occupation of the AP-1 binding site in vivo. The hormone receptor acts without itself binding to DNA.

Base Sequence↗
PubMed1992

Steroids and growth promoting factors in the regulation of expression of genes and gene networks.

Steroid hormones and growth promoting factors regulate the expression of a number of genes involved in cellular growth and differentiation. In many cases, cellular proliferation and differentiation-specific pathways are mutually exclusive. As an example for the mechanism of mutual exclusion, transcription factors responsible for pathway-specific gene expression interact with each other. Steroid hormone receptors inhibit the action of the transcription factor AP-1 (Fos/Jun) and vice versa. This inhibitory interaction is predominantly effected at the level of protein-protein contact without the need for the interfering transcription factor to bind to DNA. In some cases the two pathways function additively or even synergistically resulting in cooperation of the transcription factors in regulation of gene expression. The examples to be discussed in this text document how elaborate and important cross-talks between signal transduction pathways are. This is particularly demonstrated by the fine tuning and reversibility of these processes.

Animals↗
PubMed1992

Ultraviolet-radiation induced c-jun gene transcription: two AP-1 like binding sites mediate the response.

In HeLa cells transcription of the c-jun gene is activated strongly and rapidly by ultraviolet (UV) irradiation and, to a somewhat lesser extent, by treatment with phorbol ester tumor promoters. In the same cells UV and phorbol esters only marginally enhance the abundance of RNA transcribed from the jun D gene and from the gene coding for the serum response factor (which in turn acts on the UV and phorbol ester response element of the c-fos gene). In contrast to c-jun, jun B transcription is induced more efficiently by phorbol ester than by UV irradiation, suggesting that the members of the jun family are differently regulated. The promoter of c-jun carries two enhancer elements resembling AP-1 binding sites: the jun1 UV response element (URE-71 TGACATCA -64) and the jun2 URE (-190 TTACCTCA-183). These elements act independently in the UV induced expression of c-jun. In the context of the complete c-jun promoter they seem not to be required for c-jun induction by phorbol esters. When fused to the Herpes simplex thymidine kinase promoter, however, the isolated elements mediate induction by both UV and phorbol esters. UV and phorbol ester treatment of cells increases the binding of transcription factors to both elements. Both elements bind factors different in modification or/and constitution from AP-1, the heterodimeric transcription factor composed of c-Fos and c-Jun that controls the activity of the UV and phorbol ester response element (-72 TGAGTCA-66) of the human collagenase gene.

Base Sequence↗
PubMed1992

Positive and negative regulation of collagenase gene expression.

Transcription of the human collagenase I gene is induced by phorbol esters and repressed by glucocorticoids. Both types of regulation are mediated by the major enhancer element of the gene, which is localized between positions -73 and -65. The enhancer suffices to transmit positive and negative signals to a heterologous promoter or to a minimal promoter carrying only the TATA-box, both detected by the appearance of chloramphenicol-acetyl-transferase transcribed from the reporter gene linked to the promoters. Sequences 5' of the enhancer modulate its activity. Up- and down-regulation of gene constructs which contain only the collagenase enhancer linked to a heterologous promoter, are independent of ongoing protein synthesis, suggesting posttranslational modification of the transcription factor binding to the enhancer. Repression by glucocorticoids depends on an activated glucocorticoid receptor; a tenfold lower glucocorticoid concentration is needed for repression of the collagenase gene as compared to the activation of the mouse mammary tumor virus long terminal repeat. Immunoprecipitates of the dexamethasone receptor contain AP-1, suggesting a direct interaction of both transcription factors; this interaction may lead to the inactivation of AP-1. The action mechanism of phorbol esters and dexamethasone confirms the central role of AP-1 in proliferation control and tumor promotion. It appears that the most effective tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and the most effective anti-tumor promoter dexamethasone exert their action through the modulation of the same transcription factor.

Base Sequence↗
PubMed1991

CD44 splice variants confer metastatic behavior in rats: homologous sequences are expressed in human tumor cell lines.

One of several splice variants of CD44 expressed in metastasizing cell lines of rat tumors has been shown to confer metastatic potential to the non-metastatic variant of a rat pancreatic carcinoma line (U. Günthert et al., Cell, 65: 13-24, 1991). The variant-specific rat CD44 sequences were used to detect RNA expression in human cell lines: in carcinoma lines from lung, breast and colon; and in keratinocyte lines. By polymerase chain reaction amplification, complementary DNAs encoding human homologues were isolated and sequenced. The largest splice variant has been found in a large cell lung carcinoma line and in keratinocyte cell lines. It carries at least 5 additional domains (exons) encoding a total of 338 amino acids in the membrane-proximal extracellular region of the standard CD44. Various alternative splice products have been detected in other human tumor cell lines. The distribution of CD44 splice variants is consistent with the speculation that they fulfill functions in only a few restricted differentiation pathways and that in tumor cells these pathways have been reactivated.

Amino Acid Sequence↗
PubMed1991

A new cAMP response element in the transcribed region of the human c-fos gene.

In NIH 3T3 cells the c-fos gene is induced rapidly and transiently by cAMP. As shown by the analysis of 3T3 cells stably transfected with promoter mutants of the human c-fos gene this induction does not depend on the dyad symmetry element (position -320 to -300), but involves at least two other non-related sites: an element located around position -60 resembling the cAMP response element of the fibronectin and somatostatin genes (which has been described before), and an element located between positions +18 and +38. Destruction of one or the other element in the c-fos gene reduces cAMP inducibility. The cAMP response of c-fos promoter CAT gene constructs also depends on these elements in transient transfection assays. When cloned in front of the albumin TATA box, both elements independently mediate cAMP inducibility. These elements do not bind the same protein as shown in gel retardation analyses, suggesting that two different cAMP inducible factors mediate the activation of the c-fos gene by cAMP.

Animals↗
PubMed1991

A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells.

Using a monoclonal antibody (MAb1.1ASML) raised against a surface glycoprotein of the metastasizing rat pancreatic carcinoma cell line BSp73ASML, cDNA clones have been isolated that encode glycoproteins with partial homology to CD44, a presumed adhesion molecule. In one of the clones, pMeta-1, the epitope marks an additional extracellular domain of 162 amino acids inserted into the rat CD44 protein between amino acid positions 223 and 247 (by analogy to human and murine CD44). The new variants are expressed only in the metastasizing cell lines of two rat tumors, the pancreatic carcinoma BSp73 and the mammary adenocarcinoma 13762NF; they are not expressed in the non-metastasizing tumor cell lines nor in most normal rat tissues. Overexpression of pMeta-1 in the nonmetastasizing BSp73AS cells suffices to establish full metastatic behavior.

Amino Acid Sequence↗
PubMed1991

Retinoic-acid-induced differentiation prevents gene amplification in teratocarcinoma stem cells.

In an attempt to study the regulatory properties of cells required for gene amplification, the capacity for amplification of the dehydrofolate reductase gene (dhfr) was determined in F9 teratocarcinoma stem cells during differentiation. By stepwise selection of surviving cells exposed to progressively increasing concentrations of methotrexate (MTX) up to 1,000 microM within 4 months, non-differentiated F9 cells reached a more than 40-fold amplification of their dhfr gene, elevated levels of dhfr mRNA and a 5-log increase in MTX resistance. Exposure to 5 Gy of 60Co-gamma-irradiation accelerated the process of amplification. In contrast, F9 cells that had been differentiated to endodermal cells by treatment with retinoic acid (RA) did not grow in MTX concentrations above 0.1 microM, either with or without radiation pretreatment and did not amplify the dhfr gene to any measurable extent over the same period of time. Upon treatment of methotrexate-resistant (F9-MTXr) cells with retinoic acid, loss of the amplified DNA in the absence of selection was significantly retarded. The ability to amplify the dhfr gene was correlated with the occurrence of origin binding activity in vitro (early domain of SV40 minimal origin of replication). These data indicate an increase in genomic stability and rigorous control of origin activity by differentiation.

Animals↗
PubMed1991

Involvement of fos in spontaneous and ultraviolet light-induced genetic changes.

Transient overexpression of ras, mos, or fos transcribed from various inducible promoters in NIH 3T3 cells causes significant increases in the frequency of chromosomal aberrations and, as shown for fos, in gene mutations. Under the experimental conditions of exponential growth and full serum supply, overexpression of the oncogenes does not increase the proliferation rate of cells. The generation of ras- and mos-induced chromosomal aberrations was suppressed in cells that had been deprived of fos protein by antisense c-fos oligodeoxynucleotides. The induction of chromosomal aberrations by ultraviolet irradiation is also suppressed by antisense c-fos oligodeoxynucleotides. The data suggest that fos protein alone, or a transcription factor that contains fos protein as a subunit, activates or induces the synthesis of one or several mutator functions. Oncogene-driven mutagenesis could account for the accumulation of additional mutations after the activation of an oncogene, which may furnish a mechanistic basis for tumor promotion and tumor progression.

3T3 Cells↗
PubMed1991

Growth control and neoplastic transformation in the brain.

For many scientists it is often difficult to predict which meetings, among the plethora convening each year, will be the most rewarding. A particular strength of the Zülch symposium was the lively exchange of novel findings and ideas among researchers tackling problems as diverse as photoreceptor cell development in Drosophila and the molecular basis of tumor metastasis. It is these small focused meetings which draw together molecular biologists, clinicians, and pathologists that bear the key to success. Both of us felt strongly that all participants took ideas back home. What else could we ask for? If Zülch had been granted the opportunity to come to Goslar, he would have enjoyed this symposium very much.

Animals↗
PubMed1990

Retardation of metastatic tumor growth after immunization with metastasis-specific monoclonal antibodies.

The influence of 4 murine monoclonal antibodies (MAbs) directed against surface determinants of a metastasizing rat adenocarcinoma (BSp73ASML) on metastatic spread was evaluated and compared to their in vivo binding as well as to the induction of a humoral anti-MAb response, especially with respect to the development of anti-idiotypic (ID) antibodies of the internal image type. In a protocol of explicit immunization, all 4 MAbs transiently inhibited metastatic growth. Survival was prolonged only with one MAb (4.4ASML). With another MAb (1.1ASML), directed against a new variant form of CD44, metastatic growth was accelerated after transient retardation. Retardation of metastatic growth correlated with the humoral anti-MAb response. This accounted for the isotype- as well as for the idiotype-specific response. An exception was noted after immunization with MAb 1.1ASML. Rats with high levels of anti-1.1ASML antibodies, which inhibited binding to the tumor cells (internal image-type antibodies) showed accelerated metastatic spread. Data are interpreted to mean that MAb-induced inhibition of metastatic spread may be based on 2 independent mechanisms: blockade of metastasis-associated epitopes (i.e., with MAb 1.1ASML) and induction of an anti-mouse Ig response. In the latter case it was irrelevant whether the response was isotype- or idiotype-specific.

Adenocarcinoma↗
PubMed1990

Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone.

Glucocorticoid hormones counteract inflammation and phorbol ester tumor promotion and drastically decrease the expression of several extracellular proteases, including collagenase I. Glucocorticoid hormone inhibits basal and induced transcription of collagenase by interfering with AP-1, the major enhancer factor of the collagenase promoter. The mechanism of interference is novel in that it does not require protein synthesis, it depends on the hormone receptor but not its binding to DNA, it occurs at hormone doses one order of magnitude below those required for gene activation, and it involves down-modulation of the trans-activating function of preexisting unbound and DNA-bound AP-1. Coprecipitation experiments suggest direct AP-1-hormone receptor interaction, which also possibly explains the reverse experiment: overexpression of Fos or Jun inhibits the expression of hormone-dependent genes.

Animals↗
PubMed1990

A novel function of the transforming domain of E1a: repression of AP-1 activity.

Adenovirus E1a represses transcription of the collagenase gene via the phorbol ester-responsive element (collTRE). The mechanism involves inhibition of the trans-activating function of the transcription factor AP-1 without reduction of its synthesis and without any apparent change in DNA binding or composition. The ability of E1a to downmodulate AP-1 is a unique property among dominant oncogenes. This repression depends on conserved region 1, one of the transforming domains of E1a, indicating that it is an integral feature of adenovirus transformation.

Adenovirus Early Proteins↗
PubMed1990

Radiation-induced activation of transcription factors in mammalian cells.

In mammalian cells radiation induces the enhanced transcription of several genes. The cis acting elements in the control region of inducible genes have been delimited by site directed mutagenesis. Several different elements have been found in different genes. They do not only activate gene transcription in response to radiation but also in response to growth factors and to tumor promoter phorbol esters. The transcription factors binding to these elements are present also in non-irradiated cells, but their DNA binding activity and their transactivating capability is increased upon irradiation. The signal chain linking the primary radiation-induced signal (damaged DNA) to the activation of transcription factors involves the action of (a) protein kinase(s).

Animals↗