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Biomedical subjects

F Hesse

Publications and source records attributed to F Hesse.

16 recordsLinked to original sources
PubMed2001

Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53.

The oncoprotein MDM2 inhibits the tumor suppressor protein p53 by binding to the p53 transactivation domain. The p53 gene is inactivated in many human tumors either by mutations or by binding to oncogenic proteins. In some tumors, such as soft tissue sarcomas, overexpression of MDM2 inactivates an otherwise intact p53, disabling the genome integrity checkpoint and allowing cell cycle progression of defective cells. Disruption of the MDM2/p53 interaction leads to increased p53 levels and restored p53 transcriptional activity, indicating restoration of the genome integrity check and therapeutic potential for MDM2/p53 binding antagonists. Here, we show by multidimensional NMR spectroscopy that chalcones (1,3-diphenyl-2-propen-1-ones) are MDM2 inhibitors that bind to a subsite of the p53 binding cleft of human MDM2. Biochemical experiments showed that these compounds can disrupt the MDM2/p53 protein complex, releasing p53 from both the p53/MDM2 and DNA-bound p53/MDM2 complexes. These results thus offer a starting basis for structure-based drug design of cancer therapeutics.

Antineoplastic Agents↗
PubMed1998

[Not Available].

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Education↗
PubMed1996

Down regulation of S-adenosyl-L-methionine decarboxylase activity of Trypanosoma brucei during transition from long slender to short stumpy-like forms in axenic culture.

Long slender trypanosomes, isolated from infected mouse blood or from cryopreserved stabilates, respectively, were unable to grow in conditioned media (cMEM), prepared from the declining phase of axenic bloodstream form cultures. Additionally, mixtures of fresh medium and cMEM led to decreased growth rates and, in accordance to the amount of cMEM used, to a decreased S-adenosyl-L-methionine decarboxylase (Ado-MetDC; E.C. 4.1.1.50) activity. Since addition of polyamines could not overcome the process of transition from dividing to non-dividing cells and the intracellular S-adenosyl-L-methionine (AdoMet), ornithine and putrescine concentrations seemed unaltered during the course of cultivation, we questioned if polyamine metabolism is involved in this transition process. Activities of two key enzymes of polyamine metabolism, AdoMetDC and ornithine decarboxylase (ODC; E.C. 4.1.1.17) were therefore monitored during different growth stages. Our results revealed a specific activity of 44 pmol min-1 mg protein-1 for AdoMetDC and a KM of 10 mu M for AdoMet. Methylglyoxal bis(guanylhydrazone) showed a Ki of 6 mu M. The constant activity of the enzyme during a 7 h time-course in the presence of cycloheximide indicates a t1/2 of more than 7 h for the trypanosomal enzyme. Enzyme activity in trypanosomes isolated from infected laboratory animals and from logarithmic phase bloodstream or procyclic form cultures was high according to a high dividing rate, whereas enzyme activity in parasites isolated from the stationary phase of bloodstream from culture was negligible. In these cultures, AdoMetDC activity decreased with a t1/2 of 7 h during transition from long slender to short stumpy-like forms as soon as the stationary phase was reached. ODC activity was high (approximately 300 pmol min-1 mg protein-1) in dividing trypanosomes isolated from infected animals as well as from logarithmic phase bloodstream or procyclic form cultures and decreased also during transition with a t1/2 of 10 h.

Adenosylmethionine Decarboxylase↗
PubMed1995

A novel cultivation technique for long-term maintenance of bloodstream form trypanosomes in vitro.

We used an axenic cultivation system to grow African trypanosomes in vitro. Long-term cultivation for more than 60 days has been achieved by replacing the culture medium at regular intervals between 6 and 48 h. In contrast to a control culture without medium replacement, increasing amounts of maximum cell concentrations have been obtained, ranging from 5 x 10(6) to 2 x 10(7) trypanosomes ml-1, whereas the generation doubling time remained constant (about 6 h). Higher cell concentrations have only been obtained by total medium replacement; neither addition of fresh medium nor serum led to a higher cell yield, suggesting that a trypanosome-derived factor or metabolite accumulated in the medium rather than medium was depleted of an essential nutrient. Most interestingly, however, successive waves have been obtained which eventually led to a damped oscillation curve with a constant high population density after about 40 days of cultivation. Cultures were started with a homogeneous population of the long-slender form. As judged by light microscopy, cells showed a stumpy morphology during the declining phase and became slender again in the following growth phase. At later time points, when cells remained in a stationary phase at high population density, many different morphological stages have been observed, similar to those described by early authors as intermediate forms [Ormerod, W. E. (1979) In: Biology of the Kinetoplastida, Vol. 2, pp. 340-393], although many dividing forms are still present at that time. In contrast, identically treated procyclic cultures were unable to produce cyclic growth waves. Based on these results, a novel concept considering a possible differentiation mechanism is discussed.

Animals↗
PubMed1992

Self-peptide released from class II HLA-DR1 exhibits a hydrophobic two-residue contact motif.

Peptide fragments of foreign and self-proteins are of great immunologic importance as their binding to major histocompatibility complex (MHC) class I or II molecules makes an interaction with a corresponding T cell receptor possible. Recently, allele-specific peptide sequence motifs proved to be responsible for MHC binding, no matter whether self- or non-self-antigens were involved. Up to now, all investigated human class II-associated peptides were derived from foreign antigenic proteins. Therefore, we undertook sequence and binding analyses with a 16-mer self-peptide (SP3) that has been eluted from HLA-DR1. Here we demonstrate, by synthetic polyalanine-based 13-mer analogues of SP3, that two bulky hydrophobic anchor residues with relative spacing i, i + 8 are sufficient for high affinity binding. This is consistent with the hydrophobic i, i + 8 binding pattern recently found for DR-restricted T cell epitopes. Nevertheless, highly helical alanine-based design peptides with anchor spacing i, i + 9 exhibit maximal affinity, whereas replacement of alanine by helix destabilizing proline abrogates binding. Thus, a two-residue contact motif is the common minimal requirement of self- and foreign peptides for high affinity anchoring to HLA-DR1. In contrast to class I, the anchor spacing of DR1-associated peptides seems to bear some variability due to conformational diversity.

Amino Acid Sequence↗
PubMed1992

An auxin-binding protein is localized to the plasma membrane of maize coleoptile cells: identification by photoaffinity labeling and purification of a 23-kda polypeptide.

Plasma membrane vesicles were isolated from maize (Zea mays L.) coleoptile tissue by aqueous two-phase partitioning and assayed for homogeneity by the use of membrane-specific enzymatic assays. Using 5-azido-[7-3H]indole-3-acetic acid ([3H]N3IAA), we identified several IAA-binding proteins with molecular masses of 60 kDa (pm60), 58 kDa (pm58), and 23 kDa (pm23). Using Triton X-114, we were able to selectively extract pm23 from the plasma membrane. We show that auxins and functional analogues compete with [3H]N3IAA for binding to pm23. We found that PAB130, a polyclonal antibody raised against auxin-binding protein 1 (ABP-1), recognized ABP-1 as well as pm23. This suggests that pm23 shares common epitopes with ABP-1. In addition, we identified an auxin-binding protein with a molecular mass of 24 kDa (pm24), which was detected in microsomal but not in plasma membrane vesicle preparations. Like pm23 this protein was extracted from membrane vesicles with Triton X-114. We designed a purification scheme allowing simultaneous purification of pm23 and pm24. Homogeneous pm23 and pm24 were obtained from coleoptile extracts after 7000-fold purification.

Journal Article↗
PubMed1991

Hormonal modulation of plant growth: the role of auxin perception.

The organisation of growth and development in vascular plants appears to be highly adapted to meet the specific demands of a sessile, autotrophic habit. Many of the characteristic features of plant development are associated with the activities of five groups of phytohormones. Each of the phytohormones has the ability to influence fundamentally a remarkable variety of developmental and physiological processes. This ability has been widely documented but remains to be explained. Here we describe how recent breakthroughs in the analysis and understanding of eucaryotic signal transduction are being applied, in conjunction with technical advances in molecular genetics, to elucidate the molecular basis of the phytohormonal properties of auxin. Both auxin concentration, and the sensitivity of plant cells to this phytohormone have been implicated as important parameters in auxin action. We describe recent molecular biological approaches to assess the contribution made by each of these parameters. Emphasis is given to a description of recent genetic and biochemical progress towards identification of the molecular targets of the auxin signal and the molecular components involved in its subsequent transduction.

Endoplasmic Reticulum↗
PubMed1977

Gram stain evaluation of the quality of sputum specimens for mycobacterial culture.

A group of 34 mycobacteria, consisting of 25 Mycobacterium tuberculosis and nine strains of three other species, was isolated from 400 expectorated sputum specimens submitted on 148 patients from county-wide sources. Eight strains (24% of the total) were isolated from specimens evaluated by Gram stain to be oropharyngeal fluids. The remaining 26 strains were isolated from ungradable specimens and those primarily of lower respiratory origin. It was concluded that the random examination of sputum by Gram stain to determine the specimen's quality for mycobacterial isolation is not necessary.

Humans↗