Biomedical subjects

Hinrich Gronemeyer

Publications and source records attributed to Hinrich Gronemeyer.

9 recordsLinked to original sources

PubMed2004

Leukemia: beneficial actions of retinoids and rexinoids.

Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia, is the prototype of a cancer that can be cured by differentiation therapy using combined retinoic acid (RA) and chemotherapy. Acute promyelocytic leukemia is caused by chromosomal translocations, which in the large majority of cases generate the prototypic promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARalpha) an oncogenic fusion protein formed from the retinoic-acid receptor alpha and the so-called PML protein. The fusion protein leads to the deregulation of wild type PML and RARalpha function, thus inducing the differentiation block and an altered survival capacity of promyelocytes of affected patients. A plethora of studies have revealed molecular details that account for the oncogenic properties of acute promyelocytic leukemia fusion proteins and the events that contribute to the therapy-induced differentiation and apoptosis of patients' blasts. Illustrating the beneficial mechanisms of action of retinoids for acute promyelocytic leukemia patients this review goes on to discuss a plethora of recently recognized molecular paradigms by which retinoids and rexinoids, alone or in combination with other compounds, regulate growth, differentiation and apoptosis also in non-acute promyelocytic leukemia cells, highlighting their potential as drugs for cancer therapy and prevention.

Apoptosis↗

PubMed2003

Separation of retinoid X receptor homo- and heterodimerization functions.

As a promiscuous dimerization partner the retinoid X receptor (RXR) can contribute to signaling by multiple nuclear receptors. However, the impact of RXR cosignaling and the possible existence of an RXR homodimer signaling pathway are largely unexplored. We report here on the separation of RXR homo- and heterodimerization as an essential step towards the elucidation of the roles of RXR homo- and heterodimers in retinoid-rexinoid signaling. RXR homodimerization was specifically disrupted by single mutations in the RXR dimerization interface. In contrast, even multiple mutations did not fully impair RXR heterodimerization with retinoic acid receptor (RAR). Importantly, the mutation of mouse RXRalpha (mRXRalpha) Tyr402 substantially weakened RAR heterodimerization while concomitantly increasing homodimerization. Not only did this lead to cooperatively enhanced RXR homodimer binding to DR1 or DR5 elements, but unexpectedly, the mutant acquired significant binding efficiency for noncognate DR3 or DR4 elements as well. The increased stability of RXR homodimers on DR1 correlated with increased transcriptional activity of mRXRalpha(Y402A) on DR1-based reporter genes. Weak, if any, heterodimerization was observed with thyroid, vitamin D(3), or peroxisome proliferator-activating receptors. A model accounting for the structural impact of the Tyr402 mutation on dimerization is discussed. These results provide the basis for a genetic replacement of wild-type RXRs by mutants like mRXRalpha(Y402A) to elucidate the physiological impact of RXR homo- and heterodimerization.

Amino Acid Sequence↗

PubMed2002

PIAS3 (protein inhibitor of activated STAT-3) modulates the transcriptional activation mediated by the nuclear receptor coactivator TIF2.

PIAS3, a member of the protein inhibitor of activated STAT family, was found to interact in vivo and in vitro with TIF2, a previously described coactivator for nuclear receptors. The interaction is mediated by two distinct non-contiguous regions of TIF2. We found that TIF2-PIAS3 interaction occurs through a unique domain of PIAS3, very rich in acidic residues and conserved throughout the PIAS family. PIAS3 modulates the ability of TIF2 to mediate ligand-enhanced transcription activation positively or negatively, for different steroid receptors. Taken together, our results indicate a potential role of PIAS3 as transcriptional modulator of TIF2-mediated signalling.

Androgens↗

PubMed2002

TIF2 mediates the synergy between RARalpha 1 activation functions AF-1 and AF-2.

Nuclear receptors recruit coregulator complexes through both their AF-1 and AF-2 activation domains. Here we demonstrate that TIF2, a p160 coactivator, is able to bridge the two activation domains of the retinoic acid (RA) receptor isotype RARalpha1, resulting in synergistic activation of transcription. Bridging requires the presence of motifs in region A of RARalpha1 and in the activation domain AD1 of TIF2. Notably, only RARalpha1 exerted this interaction, which requires additional unknown factors. This is the first observation of a RAR isotype-selective coactivator interaction. Because another p160 coactivator, SRC-1, has no effect, this is also the first demonstration of a difference between the members of this coactivator family.

Animals↗

PubMed2002

Co-regulator recruitment and the mechanism of retinoic acid receptor synergy.

Crystal structure and co-regulator interaction studies have led to a general mechanistic view of the initial steps of nuclear receptor (NR) action. Agonist-induced transconformation of the ligand-binding domain (holo-LBD) leads to the formation of co-activator complexes, and destabilizes the co-repressor complexes bound to the ligand-free (apo) LBD. However, the molecular basis of retinoid-X receptor (RXR) 'subordination' in heterodimers, an essential mechanism to avoid signalling pathway promiscuity, has remained elusive. RXR, in contrast to its heterodimer partner, cannot autonomously induce transcription on binding of cognate agonists. Here we show that RXR can bind ligand and recruit co-activators as a heterodimer with apo-retinoic-acid receptor (apo-RAR). However, in the usual cellular environment co-repressors do not dissociate and they prohibit co-activator access because co-regulator binding is mutually exclusive. Accordingly, RXR subordination can be overcome in heterodimers that bind co-repressor weakly or in cells with a high co-activator content. We identify two types of RAR antagonists that differentially modulate co-regulator interaction, and we demonstrate that synergy between RAR ligands and RXR agonists results from increased interaction efficiency of a single p160 with the heterodimer, requiring two intact receptor-binding surfaces on the co-activator.

DNA-Binding Proteins↗

PubMed2002

Quality indicators increase the reliability of microarray data.

Large-scale gene expression profiling with DNA microarrays opens new dimensions to molecular biology but still lacks the overall precision of traditional low-scale techniques. We developed a novel strategy of data processing linking search stringency to quality indicators for efficient detection of low-level, regulated genes. Using retinoid-induced differentiation of NB-4 promyelocytic cells, the variation of expression profiles between biological duplicates was studied and compared with the changes induced by all-trans retinoic acid (atRA) treatment. An analysis of 4320 genes showed that retinoic acid has mainly geneactivating function in NB-4 cells. Treatment with atRA for 18 hours induced metabolic genes that may be associated with cell differentiation and signaling factors triggering later events leading to apoptosis; cytokine genes were among the highest stimulated by atRA. Notably, we identified a regulatory loop inhibiting MYC action: as MYC was downregulated, a cognate repressor of MYC was upregulated.

Cluster Analysis↗

PubMed2002

Decryption of the retinoid death code in leukemia.

The recent elucidation of several molecular paradigms by which retinoids regulate growth, differentiation, and apoptosis highlights their promise as drugs for cancer therapy and prevention. Several novel signaling pathways by which retinoids induce cell death have been identified recently. They comprise (a) the induction by RARalpha-selective retinoids of the tumor-selective death ligand TRAIL that kills acute promyelocytic leukemia (APL) cells in a paracrine mode of action, which is the cause of retinoic acid-induced apoptosis after maturation: (b) a novel RARalpha-independent rexinoid-PKA cross-talk that induces maturation of both ATRA-sensitive and ATRA-resistant APL cells and does not invoke ligand-induced alteration of PML-RARalpha signaling, stability, or compartmentalization; and (c) a novel rexinoid signaling pathway that triggers apoptosis of immature APL cells and may correspond to a default death pathway that is operative in the absence of "survival" factors. This rexinoid apoptosis is inhibited by RXR but not RAR antagonists and is distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis. Here we discuss the promise of retinoids for cancer treatment and prevention with an emphasis on the recently identified mechanisms by which they control (cancer) cell proliferation.

Apoptosis↗

PubMed2002

The function of TIF2/GRIP1 in mouse reproduction is distinct from those of SRC-1 and p/CIP.

Human TIF2 (hTIF2) is a member of the p160 family of nuclear receptor coactivators, which includes SRC-1 and p/CIP. Although the functions of hTIF2 and of its mouse homolog (GRIP1 or mTIF2) have been clearly established in vitro, their physiological role remains elusive. Here, we have generated mice lacking mTIF2/GRIP1 and examined their phenotype with a particular emphasis on reproductive functions. TIF2(-/-) mice are viable, but the fertility of both sexes is impaired. Male hypofertility is due to defects in both spermiogenesis (teratozoospermia) and age-dependent testicular degeneration, and TIF2 expression appears to be essential for adhesion of Sertoli cells to germ cells. Female hypofertility is due to a placental hypoplasia that most probably reflects a requirement for maternal TIF2 in decidua stromal cells that face the developing placenta. We conclude that TIF2 plays a critical role in mouse reproductive functions, whereas previous reports have not revealed serious fertility impairment in SRC-1(-/-) or p/CIP(-/-) mutants. Thus, even though the three p160 coactivators exhibit strong sequence homology and similar activity in assays in vitro, they play distinct physiological roles in vivo, as their genetic eliminations result in distinct pathologies.

Age Factors↗

PubMed2002

The retinoic acid signaling pathway regulates anterior/posterior patterning in the nerve cord and pharynx of amphioxus, a chordate lacking neural crest.

Amphioxus, the closest living invertebrate relative of the vertebrates, has a notochord, segmental axial musculature, pharyngeal gill slits and dorsal hollow nerve cord, but lacks neural crest. In amphioxus, as in vertebrates, exogenous retinoic acid (RA) posteriorizes the embryo. The mouth and gill slits never form, AmphiPax1, which is normally downregulated where gill slits form, remains upregulated and AmphiHox1 expression shifts anteriorly in the nerve cord. To dissect the role of RA signaling in patterning chordate embryos, we have cloned the single retinoic acid receptor (AmphiRAR), retinoid X receptor (AmphiRXR) and an orphan receptor (AmphiTR2/4) from amphioxus. AmphiTR2/4 inhibits AmphiRAR-AmphiRXR-mediated transactivation in the presence of RA by competing for DR5 or IR7 retinoic acid response elements (RAREs). The 5' untranslated region of AmphiTR2/4 contains an IR7 element, suggesting possible auto- and RA-regulation. The patterns of AmphiTR2/4 and AmphiRAR expression during embryogenesis are largely complementary: AmphiTR2/4 is strongly expressed in the cerebral vesicle (homologous to the diencephalon plus anterior midbrain), while AmphiRAR expression is high in the equivalent of the hindbrain and spinal cord. Similarly, while AmphiTR2/4 is expressed most strongly in the anterior and posterior thirds of the endoderm, the highest AmphiRAR expression is in the middle third. Expression of AmphiRAR is upregulated by exogenous RA and completely downregulated by the RA antagonist BMS009. Moreover, BMS009 expands the pharynx posteriorly; the first three gill slit primordia are elongated and shifted posteriorly, but do not penetrate, and additional, non-penetrating gill slit primordia are induced. Thus, in an organism without neural crest, initiation and penetration of gill slits appear to be separate events mediated by distinct levels of RA signaling in the pharyngeal endoderm. Although these compounds have little effect on levels of AmphiTR2/4 expression, RA shifts pharyngeal expression of AmphiTR2/4 anteriorly, while BMS009 extends it posteriorly. Collectively, our results suggest a model for anteroposterior patterning of the amphioxus nerve cord and pharynx, which is probably applicable to vertebrates as well, in which a low anterior level of AmphiRAR (caused, at least in part, by competitive inhibition by AmphiTR2/4) is necessary for patterning the forebrain and formation of gill slits, the posterior extent of both being set by a sharp increase in the level of AmphiRAR. Supplemental data available on-line

Animals↗