Molekulargenetik

Fields of Interest:

  • Gene silencing and thyroid hormone in neuronal differentiation: Molecular mechanisms of gene silencing by nuclear hormone receptors and the role of corepressors in neuronal differentiation and maturation
  • Prostate cancer therapy: Molecular mechanisms of antiandrogen therapy and occurrence of therapy resistance.
  • Cellular Senescence: Molecular mechanisms of growth inhibition and induction of cellular senescence by transcriptional silencers.

 

Gene silencing and thyroid hormone in neuronal differentiation

GenrepessionThyroid hormone is an important regulator of neuronal differentiation and maturation. The receptor for thyroid hormone (TR) is a ligand regulated transcription factor mediating both gene repression and activation.
Corepressors are involved in TR-mediated gene silencing. A number of different corepressors have been described to interact with TR. Corepressors bind either in a hormone-sensitive, hormone-independent or hormone-dependent manner to TR. However, the biological functions of individual corepressors in the context of gene repression and activation as well as of TR-mediated neuronal differentiation and maturation are not known. By using functional genomics, we are analysing the selectivity and specificity of corepressors in the context of chromatin through histone modifications (acetylation, methylation, phosphorylation and ubiquitinylation) of TR target genes as well as the impact of corepressors on neuronal differentiation and maturation.

 

Prostate cancer therapy

Prostate cancer is one of the most frequent diagnosed malignancies in men and represents a significant world- wide health problem. The androgen receptor (AR) is involved in the Androgen-Insensitivity-Syndrome (disorder of male fertility), Kennedy´s Disease (neurological disorder) and in prostate cancer. AR is activated by androgens and is the key regulator in the development and progression of prostate cancer. Therefore, the AR is THE target for prostate cancer therapy.

Eventually, however, prostate cancer proliferation becomes androgen independent. At this stage the tumour no longer responds to androgen ablation and anti-androgen therapy leading to an uncontrolled progression of the disease. Importantly, the proliferation of the androgen refractory prostate cancer cells remain dependent on functional AR. The AR is target for corepressor action and anti-hormone agonism. Mol. Endocrinol. 16, 661-673. Recent evidence revealed that in refractory cancer the AR is transcriptionally active, despite reduced levels or lack of androgens. Mechanistic studies show that AR can be activated in a ligand-independent manner through different cellular pathways and membrane tyrosine kinases. Thus, THE important and main goal in prostate cancer therapy is to permanently inactivate the AR.

We analyse the molecular mechanisms of antiandrogen therapy and the signal transduction pathways that lead to dissociation of corepressors from AR and to re-activation of AR. Furthermore, we employ new strategies to inactivate human AR permanently independent of different cellular pathways and membrane tyrosine kinases.

 

Cellular Senescence

Cellular senescence is a phenomenon that describes the replicative ageing of primary cells leading to stop of proliferation and dramatic changes of cellular morphology. Specific factors are known to have the capacity to induce premature senescence. We are analysing tumour suppressors, such as the inhibitor of growth. ING1 was identified as an inhibitor of growth and has been described as a tumor suppressor. The expression of ING1 is induced in senescent cells. ING1 plays as an important role in cell cycle control. Interestingly, ING1 is a potent transcriptional silencer that is associated with histone deacetylase activity, a function that is connected to gene silencing and epigenetic inheritance. We are analyzing the molecular mechanisms of ING-mediated gene silencing and its role in cellular senescence.