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Biomedical subjects

K Van Orden

Publications and source records attributed to K Van Orden.

6 recordsLinked to original sources
PubMed2000

Insight into the tumor suppressor function of CBP through the viral oncoprotein tax.

CREB binding protein (CBP) is a cellular coactivator protein that regulates essentially all known pathways of gene expression. The transcriptional coactivator properties of CBP are utilized by at least 25 different transcription factors representing nearly all known classes of DNA binding proteins. Once bound to their target genes, these transcription factors are believed to tether CBP to the promoter, leading to activated transcription. CBP functions to stimulate transcription through direct recruitment of the general transcription machinery as well as acetylation of both histone and transcription factor substrates. Recent observations indicate that a critical dosage of CBP is required for normal development and tumor suppression, and that perturbations in CBP concentrations may disrupt cellular homeostasis. Furthermore, there is accumulating evidence that CBP deregulation plays a direct role in hematopoietic malignancies. However, the molecular events linking CBP deregulation and malignant transformation are unclear. Further insight into the function of CBP, and its role as a tumor suppressor, can be gained through recent studies of the human T-cell leukemia virus, type I (HTLV-I) Tax oncoprotein. Tax is known to utilize CBP to stimulate transcription from the viral promoter. However, recent data suggest that as a consequence of the Tax-CBP interaction, many cellular transcription factor pathways may be deregulated. Tax disruption of CBP function may play a key role in transformation of the HTLV-I-infected cell. Thus, Tax derailment of CBP may lend important information about the tumor suppressor properties of CBP and serve as a model for the role of CBP in hematopoietic malignancies.

Animals↗
PubMed1999

Binding of p53 to the KIX domain of CREB binding protein. A potential link to human T-cell leukemia virus, type I-associated leukemogenesis.

The pleiotropic cellular coactivator CREB binding protein (CBP) plays a critical role in supporting p53-dependent tumor suppressor functions. p53 has been shown to directly interact with a carboxyl-terminal region of CBP for recruitment of the coactivator to p53-responsive genes. In this report, we identify the KIX domain as a new p53 contact point on CBP. We show that both recombinant and endogenous forms of p53 specifically interact with KIX. We demonstrate that the activation domain of p53 participates in KIX binding and provide evidence showing that this interaction is critical for p53 transactivation function. The human T-cell leukemia virus, type-I-encoded oncoprotein Tax is a well established repressor of p53 transcription function. Like p53, Tax also binds to KIX. The finding that both transcription factors bind to a common region of CBP suggests that coactivator competition may account for the observed repression. We demonstrate reciprocal repression between Tax and p53 in transient transfection assays, supporting the idea of intracellular coactivator competition. We biochemically confirm coactivator competition by directly showing that both transcription factors bind to KIX in a mutually exclusive fashion. These data provide molecular evidence for the observed intracellular competition and suggest that Tax inhibits p53 function by abrogating a novel p53-KIX interaction. Thus, Tax competition for the p53-KIX complex may be a pivotal event in the human T-cell leukemia virus, type I transformation pathway.

Binding, Competitive↗
PubMed1999

Binding of the human T-cell leukemia virus Tax protein to the coactivator CBP interferes with CBP-mediated transcriptional control.

The HTLV-I oncoprotein Tax is required for high level viral transcription and is strongly linked to HTLV-I-associated malignant transformation. Tax stimulates HTLV-I transcription through high affinity binding to the KIX domain of CBP, a pleiotropic coactivator. Several cellular proteins, including c-jun, also bind to KIX and utilize CBP as a coactivator. To test whether Tax binding to KIX may disable cellular CBP function, we examined the potential interplay between Tax and c-jun for binding to KIX. We show that Tax represses the transcription function of c-jun in vivo and demonstrate that both transcription factors bind to an overlapping minimal region of KIX in vitro. c-jun binding to KIX is displaced by Tax, indicating that their binding is mutually exclusive and providing a molecular basis for the observed repression. The competition between Tax and cellular transcription factors for CBP represents a novel pathway for HTLV-I dependent deregulation of gene expression, and may have significant implications for cellular homeostasis and transformation in the HTLV-I infected T-cell.

Binding Sites↗
PubMed1987

Selective attenuation in brightness for brief stimuli and at low intensities supports age-related transient channel losses.

A brightness estimation experiment was conducted on 10 old (ages 60 to 77) and 10 young (ages 22 to 27) volunteers. Participants were introduced to magnitude estimation by scaling the lengths of line stimuli, after which they dark adapted for 10 minutes. Stimuli for brightness estimation were presented binocularly via a free-viewing system and consisted of circular flashes of 2 degrees. Stimuli covered a 3 log unit range of luminance levels in 0.5 log unit steps, and 3 durations (10, 100, 1000 msec). Linear regression analysis yielded dual-branched functions with a low intensity segment which was significantly steeper in slope than the high intensity segment. The slope for the older group was significantly less steep than that of the younger observers only at the low intensity segment. Findings with respect to stimulus duration showed a significantly attenuated slope for the old as compared to the young group only at 10 msec. The results extend previous threshold results to suprathreshold levels, and are consistent with an hypothesis of a selective loss of transient channels with age.

Adult↗
PubMed1986

Older observers have attenuated increment thresholds upon transient backgrounds.

Foveal increment thresholds were measured in young, middle-aged, and older observers. These thresholds, which involved the detection of a small test flash as a function of the intensity of a larger background adapting field (AF), were measured at the instant of onset of the AF (transient condition) and when the eye had been fully light adapted to the AF (steady-state condition). All stimuli were presented to the left eye in a free-viewing system through a 2 mm artificial pupil. For the steady-state condition for all age groups, the functions were similar, but for the transient condition, the slope for the older observers was significantly less steep than that for the younger observers. These findings are consistent with an hypothesis of a selective loss of transient (Y) channels in the aging visual system.

Adult↗