Research Interests:
Research Interests:
The role of sirtuins in cancer has recently stimulated both considerable interest and debate. It is becoming clear that some sirtuins deacetylate important tumor suppressors thereby impinging on their activity. Human SirT1, for instance,... more
The role of sirtuins in cancer has recently stimulated both considerable interest and debate. It is becoming clear that some sirtuins deacetylate important tumor suppressors thereby impinging on their activity. Human SirT1, for instance, has been shown to deacetylate p53 in biochemical assays, and growing evidence indicates that it also performs this activity in cells. Since deacetylation of p53 correlates with a decreased p53 transcriptional function, it is conceivable that sirtuin inhibition could lead to improved tumor suppression. There are, however, still many open questions regarding, for example, whether sirtuins deacetylate those lysine residues in p53 that are critical for its activity. Preliminary observations also suggest that sirtuin‐mediated modulation of p53 can also take place indirectly through changes in cellular processes (e.g., nucleolar function and p300 activity) known to affect p53. It also remains unclear whether depletion in the activity of a single sirtuin suffices to stabilize and activate p53 substantially or additional changes in other factors (including other sirtuins) are required. Finally, data from SIRT1‐knockout mice demonstrate that sustained depletion of SirT1 can give rise to genomic instability and that, therefore, SirT1 acts as a tumor suppressor. This observation implies that the safety of therapeutic interventions based on SirT1 inhibition need to be evaluated. Here we review and examine the available data on the regulation of p53 by sirtuins and on the changes in sirtuin function in tumor cells, and discuss whether pharmacological inhibition of sirtuin activity constitutes an adequate approach for cancer treatment.
Research Interests:
Malignant melanoma is the most dangerous type of skin cancer. Although recent progress in treatment has been achieved, lack of response, drug resistance and relapse remain major problems. The tumor suppressor p53 is rarely mutated in... more
Malignant melanoma is the most dangerous type of skin cancer. Although recent progress in treatment has been achieved, lack of response, drug resistance and relapse remain major problems. The tumor suppressor p53 is rarely mutated in melanoma, yet it is inactive in the majority of cases due to dysregulation of upstream pathways. Thus, we screened for compounds that can activate p53 in melanoma cells. Here we describe effects of the small molecule MJ25 (2-{[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]thio}-1,3-benzoxazole), which increased the level of p53-dependent transactivation both as a single agent and in combination with nutlin-3. Furthermore, MJ25 showed potent cytotoxicity towards melanoma cell lines, whilst having weaker effects against human normal cells. MJ25 was also identified in an independent screen as an inhibitor of thioredoxin reductase 1 (TrxR1), an important selenoenzyme in the control of oxidative stress and redox regulation. The well-characterized TrxR inhibitor aur...
The p53 tumour suppressor plays key regulatory roles in various fundamental biological processes, including development, ageing and cell differentiation. It is therefore known as the guardian of the genome and is currently the most... more
The p53 tumour suppressor plays key regulatory roles in various fundamental biological processes, including development, ageing and cell differentiation. It is therefore known as the guardian of the genome and is currently the most extensively studied protein ...
Research Interests:
Research Interests:
Cervical cancer is a major cause of death in women worldwide and is strongly associated with human papillomavirus (HPV) infection. Integration of HPV is thought to be a key step in malignant progression, and is associated with loss of... more
Cervical cancer is a major cause of death in women worldwide and is strongly associated with human papillomavirus (HPV) infection. Integration of HPV is thought to be a key step in malignant progression, and is associated with loss of regulation of the viral E6 and E7 oncogenes. Leptomycin B (LMB), a nuclear export inhibitor, has previously been shown to induce apoptosis in primary keratinocytes transduced with the HPV 16 E7 or E6/E7 genes, but not in normal cells. We show here that LMB can also induce apoptosis in derivatives of the W12 cell line that contain either episomal or integrated HPV 16. Cells transduced with HPV 16 E7 or E6/E7, and the episomal and integrated W12 derivatives showed distinct temporal expression patterns of the apoptotic markers activated caspase-3 and M30. The expression of both markers occurred later in the episomal derivatives than in either transduced cells or W12 derivatives containing integrated HPV. These findings suggest that, although LMB can induce apoptosis in keratinocytes containing episomal or integrated HPV 16, genome status is likely to influence the response of HPV-associated anogenital lesions to LMB treatment.
Research Interests:
Research Interests:
Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the... more
Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and
Research Interests:
Research Interests: Virology, RNA viruses, Biological Sciences, Mutation, Escherichia coli, and 11 moreMonoclonal Antibodies, Proteins, Plasmids, Plant viruses, Molecular cloning, Substrate Specificity, Amino Acid Sequence, Base Sequence, Biochemistry and cell biology, Gene Expression Regulation, and Proteolytic activity
Research Interests:
Research Interests:
In vitro, high-risk human papillomavirus E6 proteins have been shown, in conjunction with E6-associated protein (E6AP), to mediate ubiquitination of p53 and its degradation by the 26S proteasome by a pathway that is thought to be... more
In vitro, high-risk human papillomavirus E6 proteins have been shown, in conjunction with E6-associated protein (E6AP), to mediate ubiquitination of p53 and its degradation by the 26S proteasome by a pathway that is thought to be analogous to Mdm2-mediated p53 degradation. However, differences in the requirements of E6/E6AP and Mdm2 to promote the degradation of p53, both in vivo and in vitro, suggest that these two E3 ligases may promote p53 degradation by distinct pathways. Using tools that disrupt ubiquitination and degradation, clear differences between E6- and Mdm2-mediated p53 degradation are presented. The consistent failure to fully protect p53 protein from E6-mediated degradation by disrupting the ubiquitin-degradation pathway provides the first evidence of an E6-dependent, ubiquitin-independent, p53 degradation pathway in vivo.
Research Interests:
Research Interests:
Research Interests:
Thecylindrical inclusion protein ofpotyviruses contains theso-called nucleoside triphosphate binding motif, an amino acidsequencemotifpresent inproteins encoded bymostpositive-strand RNA viruses, some double-strand RNA viruses,... more
Thecylindrical inclusion protein ofpotyviruses contains theso-called nucleoside triphosphate binding motif, an amino acidsequencemotifpresent inproteins encoded bymostpositive-strand RNA viruses, some double-strand RNA viruses, apparentlyallgroupsofdouble-strand DNAviruses, andalso several single-strand DNA viruses. Further sequenceanalysis hasallowed toinclude thecylindrical inclusion protein ofpotyviruses as a memberofa superfamily ofhelicaselike proteins. Inthis paper we showthatthepurified cylindrical inclusion protein ofplumpox potyvirus interacts withRNA andATP andcopurifies witha nucleic acid-stimulated ATPaseactivity. Toourknowledge, this isthefirst timethat this kindofenzymatic activity has beenexperimentally associated with a positive-strand RNA virus-encoded protein. Several sourcesofinformation haveledtohypotheses abouttheinvolvement ofdifferent protein activities inthe life cycle ofRNA viruses. Recent technical advances have madeitpossible forseveral ofthese proposals t...
Research Interests:
Research Interests:
Research Interests:
Activation of the p53 tumour suppressor is predicted to have therapeutically beneficial effects. Many current anti-cancer therapies activate the p53 response via DNA damage. Non-genotoxic activation of the p53 pathway would open the way... more
Activation of the p53 tumour suppressor is predicted to have therapeutically beneficial effects. Many current anti-cancer therapies activate the p53 response via DNA damage. Non-genotoxic activation of the p53 pathway would open the way to long-term and possibly prophylactic treatments. We have established a simple protocol to screen small compound libraries for activators of p53-dependent transcription, and to select and characterise the most interesting hits, which include non-genotoxic activators. These compounds or their derivatives are of potential clinical interest. This approach may also lead to the identification of novel p53-activating compound families and possibly to the description of novel molecular pathways regulating p53 activity.
Research Interests: Cancer, DNA damage, Transcription, Screening, Humans, and 5 moreMice, Animals, Comet Assay, Neoplasms, and Human Fibroblasts
Research Interests:
Research Interests: Virology, RNA viruses, Biological Sciences, Mutation, Escherichia coli, and 11 moreMonoclonal Antibodies, Proteins, Plasmids, Plant viruses, Molecular cloning, Substrate Specificity, Amino Acid Sequence, Base Sequence, Biochemistry and cell biology, Gene Expression Regulation, and Proteolytic activity
Research Interests: Mass Spectrometry, Cell Cycle, DNA repair, Fluorescence Resonance Energy Transfer, DNA, and 15 moreCell line, Humans, Mice, Animals, Peptides, Ribosomal proteins, Streptavidin, Chemical Precipitation, Ubiquitin ligase, Amino Acid Sequence, Protein Binding, Ribosomal Protein, Biochemistry and cell biology, Biotinylation, and Ubiquitination
Research Interests:
Research Interests: Cancer, Breast Cancer, Cancer Research, Mammals, Saccharomyces cerevisiae, and 14 moreHumans, Genetic Testing, Animals, Genetic Screening, Breast Cancer Research, Sirtuins, Validation Studies, Tenascin-C, Cancer Cell, Water soluble polymers, Mechanism of action, Tumor Growth, Sirtuin, and Neurosciences
Research Interests:
... E-mail: slain@uao.edu.co, santiago.lain@gmail.com, E-mail: bquintero@uao.edu.co II Martin-Luther Universität Halle-Wittenberg, Zentrum für Verfahrenstechnik, FB IW, 06099 Halle (Saale), Germany. E-mail:... more
... E-mail: slain@uao.edu.co, santiago.lain@gmail.com, E-mail: bquintero@uao.edu.co II Martin-Luther Universität Halle-Wittenberg, Zentrum für Verfahrenstechnik, FB IW, 06099 Halle (Saale), Germany. E-mail: Martin.Sommerfeld@iw.uni-halle.de. ABSTRACT. ...
Research Interests:
The behaviour of spherical solid particles in a horizontal channel flow is analysed using numerical calculations based on the Lagrangian approach. Recent developments in modelling particle motion, wall collisions, and inter-particle... more
The behaviour of spherical solid particles in a horizontal channel flow is analysed using numerical calculations based on the Lagrangian approach. Recent developments in modelling particle motion, wall collisions, and inter-particle collisions are accounted for. The wall roughness model relies on the assumption that the impact angle is composed of the particle trajectory angle and a stochastic component due to wall roughness. A stochastic approach is used to decide on the occurrence of inter- particle collisions between the considered particle and a fictitious collision partner which is a representative of the local particle phase. Then the collision probability is calculated on the basis of kinetic theory, but accounting for the velocity correlation of colliding particles. It is demonstrated that both effects, i.e. wall roughness and inter-particle collisions have a dramatic influence on the particle behaviour in a horizontal channel and the properties of the developed flow. Moreover, the calculations are compared with detailed measurements by phase-Doppler anemometry (PDA) in a horizontal channel with a height of 35 mm and a length of 6 m.
Research Interests:
... Verfahrenstechnik, Fachbereich Ingenieurwissenschaften, Martin-Luther-Universität Halle-Wittenberg, D-06099 Halle (Saale), Germany. 2 Fluid Mechanics Research Group, Universidad Autónoma de Occidente (UAO), Cali, Colombia. Email: S.... more
... Verfahrenstechnik, Fachbereich Ingenieurwissenschaften, Martin-Luther-Universität Halle-Wittenberg, D-06099 Halle (Saale), Germany. 2 Fluid Mechanics Research Group, Universidad Autónoma de Occidente (UAO), Cali, Colombia. Email: S. Laín (santiago.lain@gmail. ...