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K Hofman

Publications and source records attributed to K Hofman.

14 recordsLinked to original sources
PubMed2003

The retinoblastoma protein-associated transcription repressor RBaK interacts with the androgen receptor and enhances its transcriptional activity.

In search of potential androgen receptor coregulators we performed a yeast two-hybrid screening using the androgen receptor ligand-binding domain as bait and a human prostate cDNA library as prey and found that the carboxy-terminal domain of retinoblastoma-associated Krüppel protein (RbaK), a member of the Krüppel zinc finger protein family, interacts in a ligand-dependent way with the ligand-binding domain of the androgen receptor. RBaK was recently identified as a transcriptional regulator that interacts with the retinoblastoma protein and thereby influences E2F regulated transcription. The interaction of RBaK with the androgen receptor was further documented using mammalian two-hybrid experiments, in vitro binding studies and coimmunoprecipitation. Finally, we demonstrated that both RBaK and the retinoblastoma protein coactivate androgen receptor-mediated transcription in cotransfection experiments. In conclusion, our data show that RBaK interacts with the androgen receptor and increases its transcriptional activity. Moreover, the double interaction of RBaK with the retinoblastoma protein and with the androgen receptor provides a novel link between the androgen receptor and the regulation of the cell cycle.

Animals↗
PubMed2001

E2F activity is biphasically regulated by androgens in LNCaP cells.

Androgens exert a peculiar biphasic dose-dependent influence on the proliferation of LNCaP cells, a widely used model to study androgen effects on prostate cancer cells. Low concentrations of androgen stimulate proliferation, but high concentrations inhibit proliferation and induce strong expression of differentiation markers. In order to gain more insight into the molecular mechanisms that underlie these changes we studied the influence of a wide concentration range of the synthetic androgen R1881 on several cell cycle- and differentiation-related parameters. Low concentrations (0.1 nM), known to promote LNCaP cell proliferation, induce an increase of Retinoblastoma protein phosphorylation, accompanied by an increase of E2F-1 protein levels and E2F activity and by increased expression of the E2F-target gene products E2F-1 and cyclin A. High concentrations of R1881 (10 nM) induce strong expression of the differentiation marker prostate-specific antigen. Retinoblastoma protein is largely hypophosphorylated, resulting in low E2F activity and low concentrations of E2F-1 and cyclin A mRNA. Finally, there is a strong increase of p27(KIP1) protein, but not of p27(KIP1) mRNA. These results indicate that the biphasic dose response of LNCaP proliferation to androgen is closely reflected in Rb phosphorylation, E2F activity and p27(KIP1) protein expression.

Androgens↗
PubMed2000

Apparent coactivation due to interference of expression constructs with nuclear receptor expression.

Transient cotransfection in COS-7 cells, a standard approach to demonstrate coactivation, was used to study the coactivation properties of NuRIP183, a new nuclear receptor interacting protein of 183 kDa, isolated by a yeast two-hybrid screening. Transfection with a NuRIP183 expression construct strongly increased the ligand-dependent response of reporter constructs for several nuclear receptors when compared to transfection with the empty expression vector. A more detailed study, however, revealed major changes in the expression level of the nuclear receptors in cotransfection experiments, indicating that the observed changes in receptor activity were not due to coactivation but to differences in receptor concentration caused by interference from the cotransfected expression constructs with the expression of the receptor. Such interference, which is inversely related to the length of the insert, was observed, not only in COS-7 cells but also in CV-1 and MCF-7 cells, using different transfection techniques (FuGENE-6 and calcium phosphate) and different expression vectors (pSG5, pcDNA1.1 and pIRESneo). These data cast some doubt on coactivation of nuclear receptors based on similar cotransfection experiments without measurement of receptor concentration. Moreover, it is recommended to limit the amounts of (co)transfected expression plasmid and to avoid the use of empty expression plasmid as a control. Finally, one should be aware of similar misleading results in other experimental set-ups based on cotransfection.

Animals↗
PubMed1996

Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1.

To address the controversy regarding the relationship between cognitive impairment (lowering of IQ) and magnetic resonance imaging (MRI) characteristics (T2-weighted hyperintensities or unidentified bright objects [UBOs]) in children with neurofibromatosis-1 (NF-1), we used a pairwise NF-1/ sibling design; we set out to predict the lowering of IQ in each child with NF-1 as a discrepancy from the IQ of an unaffected sibling (D-SIQ). Our multiple regression model included the age of the child with NF-1, familial or sporadic nature of the NF-1, number of locations in the child's brain occupied by T2-weighted hyperintensities (UBOs), and the volumetric percentage of brain tissue occupied by T2-weighted hyperintensities (UBOs). Only the number of locations occupied by UBOs accounted for IQ lowering (D-SIQ) in children with NF-1 (42% of the variance in D-SIQ). This is the first report to confirm that a continuum of lowered IQs in NF-1-affected children exists in relation to the distribution of UBOs (range 0-7), not just presence (vs. absence) of any UBOs.

Adolescent↗
PubMed1994

Neurofibromatosis type 1: the evolution of deep gray and white matter MR abnormalities.

PURPOSE: To investigate the evolution of deeply located high-signal-intensity abnormalities of the brain on T2-weighted MR images of patients with neurofibromatosis type 1 (NF-1). METHODS: The study consists of two patient groups: 1) retrospective evaluation of MR scans of 24 symptomatic NF-1 patients, 10 of whom were sequentially studied, and 2) prospective MR evaluations of 20 asymptomatic NF-1 subjects from 14 families; 2 of these families were sequentially studied. RESULTS: Deeply located, high-signal-intensity abnormalities on T2-weighted images were noted in 34 of 44 NF-1 subjects (77%). If NF-1 patients are grouped according to age, 28 of 30 subjects (93%) younger than 15 years had the lesions, whereas 4 of 7 subjects (57%) between 16 and 30 years, and 2 of 7 subjects (29%) older than 31 years had lesions. High-signal lesions in basal ganglia and brain stem were demonstrated in all decades with relatively high frequency. Lesions in the cerebellar white matter and dentate nuclei were mainly found in the patients younger than 10 years, and never found after the third decade. In 13 sequential studies (mean interval, 24 months), lesions appeared to increase in size in 3, remain unchanged in size in 2, and decrease in size in 7. One subject showed a mixed pattern of lesion size change. CONCLUSIONS: Deeply located high-signal-intensity lesions on T2-weighted MR images are more evident in young NF-1 patients. The underlying brain abnormality, while pathologically unproved, is probably transient.

Adolescent↗
PubMed1993

A novel disease with deficiency of mitochondrial very-long-chain acyl-CoA dehydrogenase.

Palmitoyl-CoA dehydrogenase activity in skin fibroblasts from seven patients with unidentified defects of fatty acid oxidation was measured in the presence and absence of antibodies against medium-chain, long-chain, and very-long-chain acyl-CoA dehydrogenases (VLCAD). Two of the patients, 4-5 month old boys, were found to have a novel disease, VLCAD deficiency, as judged from the results of very low palmitoyl-CoA dehydrogenase activity and the lack of immunoreactivity toward antibody raised to purified VLCAD.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1980

Bone marrow damage due to melphalan and other cytostatic agents.

The case histories of 4 patients who developed bone marrow damage after therapy with melphalan are described. In 3 patients bone marrow damage manifested initially as a sideroblastic anaemia which was later followed by acute myeloid leukaemia. The last patient developed a dyserythropoietic anaemia with leucopenia, but thus far there has been no further progression. None of the 4 patients had any haematological abnormality prior to the melphalan therapy. Two were suffering from carcinoma of the breast and 2 had ovarian neoplasms. The fact that melphalan was given as adjuvant therapy in all 4 patients prior to the development of the haematological abnormalities supports the concept that it was of aetiological importance. These findings are in line with a number of reports in the literature in which acute leukaemia has developed in subjects treated for malignant tumours (especially multiple myeloma and ovarian cancer) with melphalan.

Acute Disease↗