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1.  Brief Cortical Deactivation Early in Life Has Long-Lasting Effects on Multisensory Behavior 
The Journal of Neuroscience  2014;34(21):7198-7202.
Detecting and locating environmental events are markedly enhanced by the midbrain's ability to integrate visual and auditory cues. Its capacity for multisensory integration develops in cats 1–4 months after birth but only after acquiring extensive visual–auditory experience. However, briefly deactivating specific regions of association cortex during this period induced long-term disruption of this maturational process, such that even 1 year later animals were unable to integrate visual and auditory cues to enhance their behavioral performance. The data from this animal model reveal a window of sensitivity within which association cortex mediates the encoding of cross-modal experience in the midbrain. Surprisingly, however, 3 years later, and without any additional intervention, the capacity appeared fully developed. This suggests that, although sensitivity degrades with age, the potential for acquiring or modifying multisensory integration capabilities extends well into adulthood.
PMCID: PMC4028497  PMID: 24849354
colliculus; cross-modal; enhancement; multisensory; orientation; plasticity
2.  Development of multisensory integration from the perspective of the individual neuron 
Nature reviews. Neuroscience  2014;15(8):520-535.
The ability to use cues from multiple senses in concert is a fundamental aspect of brain function. It maximizes the brain’s use of the information available to it at any given moment and enhances the physiological salience of external events. Because each sense conveys a unique perspective of the external world, synthesizing information across senses affords computational benefits that cannot otherwise be achieved. Multisensory integration not only has substantial survival value but can also create unique experiences that emerge when signals from different sensory channels are bound together. However, neurons in a newborn’s brain are not capable of multisensory integration, and studies in the midbrain have shown that the development of this process is not predetermined. Rather, its emergence and maturation critically depend on cross-modal experiences that alter the underlying neural circuit in such a way that optimizes multisensory integrative capabilities for the environment in which the animal will function.
PMCID: PMC4215474  PMID: 25158358
3.  A model of the temporal dynamics of multisensory enhancement 
The senses transduce different forms of environmental energy, and the brain synthesizes information across them to enhance responses to salient biological events. We hypothesize that the potency of multisensory integration is attributable to the convergence of independent and temporally aligned signals derived from cross-modal stimulus configurations onto multisensory neurons. The temporal profile of multisensory integration in neurons of the deep superior colliculus (SC) is consistent with this hypothesis. The responses of these neurons to visual, auditory, and combinations of visual–auditory stimuli reveal that multisensory integration takes place in real-time; that is, the input signals are integrated as soon as they arrive at the target neuron. Interactions between cross-modal signals may appear to reflect linear or nonlinear computations on a moment-by-moment basis, the aggregate of which determines the net product of multisensory integration. Modeling observations presented here suggest that the early nonlinear components of the temporal profile of multisensory integration can be explained with a simple spiking neuron model, and do not require more sophisticated assumptions about the underlying biology. A transition from nonlinear “super-additive” computation to linear, additive computation can be accomplished via scaled inhibition. The findings provide a set of design constraints for artificial implementations seeking to exploit the basic principles and potency of biological multisensory integration in contexts of sensory substitution or augmentation.
PMCID: PMC4120822  PMID: 24374382
Multisensory; Cross-modal; Modeling; Temporal dynamics; Enhancement
4.  Development of cortical influences on superior colliculus multisensory neurons: Effects of dark-rearing 
The European journal of neuroscience  2013;37(10):1594-1601.
Rearing cats from birth to adulthood in darkness prevents neurons in the superior colliculus (SC) from developing the capability to integrate visual and non-visual (e.g., visual-auditory) inputs. Presumably, this developmental anomaly is due to a lack of experience with the combination of those cues, which is essential to form associative links between them. The visual-auditory multisensory integration capacity of SC neurons has also been shown to depend on the functional integrity of converging visual and auditory inputs from ipsilateral association cortex. Disrupting these cortico-collicular projections at any stage of life results in a pattern of outcomes similar to those found after dark-rearing: SC neurons respond to stimuli in both sensory modalities, but cannot integrate the information they provide. Thus, it is possible that dark-rearing compromises the development of these descending tectopetal connections and the essential influences they convey. However, the results of the present experiments, using cortical deactivation to assess the presence of cortico-collicular influences, demonstrate that dark-rearing does not prevent association cortex from developing robust influences over SC multisensory responses. In fact, dark-rearing may increase their potency over that observed in normally-reared animals. Nevertheless, their influences are still insufficient to support SC multisensory integration. It appears that cross-modal experience shapes the cortical influence to selectively enhance responses to cross-modal stimulus combinations that are likely to be derived from the same event. In the absence of this experience, the cortex develops an indiscriminate excitatory influence over its multisensory SC target neurons.
PMCID: PMC3660411  PMID: 23534923
Vision; Audition; Multisensory Integration; Development
5.  Noise-rearing disrupts the maturation of multisensory integration 
It is commonly believed that the ability to integrate information from different senses develops according to associative learning principles as neurons acquire experience with co-active cross-modal inputs. However, previous studies have not distinguished between requirements for co-activation versus co-variation. To determine whether cross-modal co-activation is sufficient for this purpose in visual–auditory superior colliculus (SC) neurons, animals were reared in constant omnidirectional noise. By masking most spatiotemporally discrete auditory experiences, the noise created a sensory landscape that decoupled stimulus co-activation and co-variance. Although a near-normal complement of visual–auditory SC neurons developed, the vast majority could not engage in multisensory integration, revealing that visual–auditory co-activation was insufficient for this purpose. That experience with co-varying stimuli is required for multisensory maturation is consistent with the role of the SC in detecting and locating biologically significant events, but it also seems likely that this is a general requirement for multisensory maturation throughout the brain.
PMCID: PMC3944832  PMID: 24251451
cat; cross-modal; hearing; vision
6.  Incorporating Cross-Modal Statistics in the Development and Maintenance of Multisensory Integration 
Development of multisensory integration capabilities in superior colliculus (SC) neurons was examined in cats whose visual-auditory experience was restricted to a circumscribed period during early life (postnatal day 30-8 mos). Animals were periodically exposed to visual and auditory stimuli appearing either randomly in space and time, or always in spatiotemporal concordance. At all other times animals were maintained in darkness. Physiological testing was initiated at approximately 2 years of age. Exposure to random visual and auditory stimuli proved insufficient to spur maturation of the ability to integrate cross-modal stimuli, but exposure to spatiotemporally concordant cross-modal stimuli was highly effective. The multisensory integration capabilities of neurons in the latter group resembled those of normal animals and were retained for more than 16 months in the absence of subsequent visual-auditory experience. Furthermore, the neurons were capable of integrating stimuli having physical properties differing significantly from those in the exposure set. These observations suggest that acquiring the rudiments of multisensory integration requires little more than exposure to consistent relationships between the modality-specific components of a cross-modal event, and that continued experience with such events is not necessary for their maintenance. Apparently, the statistics of cross-modal experience early in life define the spatial and temporal filters that determine if the components of cross-modal stimuli are to be integrated or treated as independent events, a crucial developmental process that determines the spatial and temporal rules by which cross-modal stimuli are integrated to enhance both sensory salience and the likelihood of eliciting an SC-mediated motor response.
PMCID: PMC3561931  PMID: 22396404
superior colliculus; plasticity; audition; vision; cross-modal
8.  A Computational Study of Multisensory Maturation in the Superior Colliculus (SC) 
Multisensory neurons in cat SC exhibit significant postnatal maturation. The first multisensory neurons to appear have large receptive fields (RFs) and cannot integrate information across sensory modalities. During the first several months of postnatal life RFs contract, responses become more robust, and neurons develop the capacity for multisensory integration. Recent data suggest that these changes depend on both sensory experience and active inputs from association cortex. Here, we extend a computational model we developed (Cuppini et al 2010) using a limited set of biologically realistic assumptions to describe how this maturational process might take place. The model assumes that during early life, cortical-SC synapses are present but not active, and that responses are driven by non-cortical inputs with very large RFs. Sensory experience is modeled by a “training phase” in which the network is repeatedly exposed to modality-specific and cross-modal stimuli at different locations. Cortical-SC synaptic weights are modified during this period as a result of Hebbian rules of potentiation and depression. The result is that RFs are reduced in size and neurons become capable of responding in adult-like fashion to modality-specific and cross-modal stimuli.
PMCID: PMC3235682  PMID: 21556818
visual-acoustic neurons; anterior ectosylvian sulcus; enhancement; Hebb rule; learning mechanisms; inverse effectiveness principle; neural network modelling
9.  Non-Stationarity in Multisensory Neurons in the Superior Colliculus  
The superior colliculus (SC) integrates information from multiple sensory modalities to facilitate the detection and localization of salient events. The efficacy of “multisensory integration” is traditionally measured by comparing the magnitude of the response elicited by a cross-modal stimulus to the responses elicited by its modality-specific component stimuli, and because there is an element of randomness in the system, these calculations are made using response values averaged over multiple stimulus presentations in an experiment. Recent evidence suggests that multisensory integration in the SC is highly plastic and these neurons adapt to specific anomalous stimulus configurations. This raises the question whether such adaptation occurs during an experiment with traditional stimulus configurations; that is, whether the state of the neuron and its integrative principles are the same at the beginning and end of the experiment, or whether they are altered as a consequence of exposure to the testing stimuli even when they are pseudo-randomly interleaved. We find that unisensory and multisensory responses do change during an experiment, and that these changes are predictable. Responses that are initially weak tend to potentiate, responses that are initially strong tend to habituate, and the efficacy of multisensory integration waxes or wanes accordingly during the experiment as predicted by the “principle of inverse effectiveness.” These changes are presumed to reflect two competing mechanisms in the SC: potentiation reflects increases in the expectation that a stimulus will occur at a given location relative to others, and habituation reflects decreases in stimulus novelty. These findings indicate plasticity in multisensory integration that allows animals to adapt to rapidly changing environmental events while suggesting important caveats in the interpretation of experimental data: the neuron studied at the beginning of an experiment is not the same at the end of it.
PMCID: PMC3131158  PMID: 21772824
multisensory; superior colliculus
10.  Challenges in Quantifying Multisensory Integration: Alternative Criteria, Models, and Inverse Effectiveness 
Single neuron studies provide one foundation for understanding many facets of multisensory integration. These studies have used a variety of criteria for identifying and quantifying multisensory integration. While a number of techniques have been used, there lacks an explicit discussion of the assumptions, criteria, and analytical methods traditionally used to define the principles of multisensory integration. This was not problematic when the field was small, but with rapid growth a number of alternative techniques and models have been introduced, each with its own criteria and sets of implicit assumptions to define and characterize what is thought to be the same phenomenon. The potential for misconception prompted this reexamination of traditional approaches in order to clarify their underlying assumptions and analytic techniques. The objective is to review the traditional quantitative methods advanced in the study of single-neuron physiology in order to appreciate the process of multisensory integration and its impact.
PMCID: PMC3056521  PMID: 19551377
Sensory; Cross-modal; Computation; Vision; Auditory; Somatosensory
11.  Semantic confusion regarding the development of multisensory integration: a practical solution 
The European journal of neuroscience  2010;31(10):1713-1720.
There is now a good deal of data from neurophysiological studies in animals and behavioral studies in human infants regarding the development of multisensory processing capabilities. Although the conclusions drawn from these different datasets sometimes appear to conflict, many of the differences are due to the use of different terms to mean the same thing and, more problematic, the use of similar terms to mean different things. Semantic issues are pervasive in the field and complicate communication among groups using different methods to study similar issues. Achieving clarity of communication among different investigative groups is essential for each to make full use of the findings of others, and an important step in this direction is to identify areas of semantic confusion. In this way investigators can be encouraged to use terms whose meaning and underlying assumptions are unambiguous because they are commonly accepted. Although this issue is of obvious importance to the large and very rapidly growing number of researchers working on multisensory processes, it is perhaps even more important to the non-cognoscenti. Those who wish to benefit from the scholarship in this field but are unfamiliar with the issues identified here are most likely to be confused by semantic inconsistencies. The current discussion attempts to document some of the more problematic of these, begin a discussion about the nature of the confusion and suggest some possible solutions.
PMCID: PMC3055172  PMID: 20584174
amodal; crossmodal; intersensory; multimodal; supramodal
12.  The Neural Basis of Multisensory Integration in the Midbrain: Its Organization and Maturation 
Hearing research  2009;258(1-2):4-15.
Multisensory Integration describes a process by which information from different sensory systems is combined to influence perception, decisions, and overt behavior. Despite a widespread appreciation of its utility in the adult, its developmental antecedents have received relatively little attention. Here we review what is known about the development of multisensory integration, with a focus on the circuitry and experiential antecedents of its development in the model system of the multisensory (i.e., deep) layers of the superior colliculus. Of particular interest here are two sets of experimental observations: 1) cortical influences appear essential for multisensory integration in the SC, and 2) postnatal experience guides its maturation. The current belief is that the experience normally gained during early life is instantiated in the cortico-SC projection, and that this is the primary route by which ecological pressures adapt SC multisensory integration to the particular environment in which it will be used.
PMCID: PMC2787841  PMID: 19345256
13.  Initiating the development of multisensory integration by manipulating sensory experience 
The multisensory integration capabilities of superior colliculus (SC) neurons emerge gradually during early postnatal life as a consequence of experience with cross-modal stimuli. Without such experience neurons become responsive to multiple sensory modalities but are unable to integrate their inputs. The present study demonstrates that neurons retain sensitivity to cross-modal experience well past the normal developmental period for acquiring multisensory integration capabilities. Experience surprisingly late in life was found to rapidly initiate the development of multisensory integration, even more rapidly than expected based on its normal developmental time course. Furthermore, the requisite experience was acquired by the anesthetized brain and in the absence of any of the stimulus-response contingencies generally associated with learning. The key experiential factor was repeated exposure to the relevant stimuli, and this required that the multiple receptive fields of a multisensory neuron encompassed the cross-modal exposure site. Simple exposure to the individual components of a cross-modal stimulus was ineffective in this regard. Furthermore, once a neuron acquired multisensory integration capabilities at the exposure site, it generalized this experience to other locations, albeit with lowered effectiveness. These observations suggest that the prolonged period during which multisensory integration normally appears is due to developmental factors in neural circuitry in addition to those required for incorporating the statistics of cross-modal events; that neurons learn a multisensory principle based on the specifics of experience and can then apply it to other stimulus conditions; and that the incorporation of this multisensory information does not depend on an alert brain.
PMCID: PMC2858413  PMID: 20371810
Dark Rearing; Colliculus; Vision; Auditory; Maturation; Plasticity
14.  Adult plasticity in multisensory neurons: Short-term experience-dependent changes in the superior colliculus 
Multisensory neurons in the superior colliculus (SC) have the capability to integrate signals that belong to the same event, despite being conveyed by different senses. They develop this capability during early life as experience is gained with the statistics of cross-modal events. These adaptations prepare the SC to deal with the cross-modal events that are likely to be encountered throughout life. Here we found that neurons in the adult SC can also adapt to experience with sequentially-ordered cross-modal (visual-auditory or auditory-visual) cues, and that they do so over short periods of time (minutes), as if adapting to a particular stimulus configuration. This short-term plasticity was evident as a rapid increase in the magnitude and duration of responses to the first stimulus, and a shortening of the latency and increase in magnitude of the responses to the second stimulus when they are presented in sequence. The result was that the two responses appeared to merge. These changes were stable in the absence of experience with competing stimulus configurations, outlasted the exposure period, and could not be induced by equivalent experience with sequential within-modal (visual-visual or auditory-auditory) stimuli. A parsimonious interpretation is that the additional SC activity provided by the second stimulus became associated with, and increased the potency of, the afferents responding to the preceding stimulus. This interpretation is consistent with the principle of spike-timing dependent plasticity (STDP), which may provide the basic mechanism for short term or long term plasticity and be operative in both the adult and neonatal SC.
PMCID: PMC2824179  PMID: 20016107
Midbrain; Multisensory; Superior; Colliculus; Plasticity; Visual; Auditory
15.  A Neural Network Model of Multisensory Integration Also Accounts for Unisensory Integration in Superior Colliculus 
Brain research  2008;1242:13-23.
Sensory integration is a characteristic feature of superior colliculus (SC) neurons. A recent neural network model of single-neuron integration derived a set of basic biological constraints sufficient to replicate a number of physiological findings pertaining to multisensory responses. The present study examined the accuracy of this model in predicting the responses of SC neurons to pairs of visual stimuli placed within their receptive fields. The accuracy of this model was compared to that of three other computational models (additive, averaging and maximum operator) previously used to fit these data. Each neuron’s behavior was assessed by examining its mean responses to the component stimuli individually and together, and each model’s performance was assessed to determine how close its prediction came to the actual mean response of each neuron and the magnitude of its predicted residual error. Predictions from the additive model significantly overshot the actual responses of SC neurons and predictions from the averaging model significantly undershot them. Only the predictions of the maximum operator and neural network model were not significantly different from the actual responses. However, the neural network model outperformed even the maximum operator model in predicting the responses of these neurons. The neural network model is derived from a larger model that also has substantial predictive power in multisensory integration, and provides a single computational vehicle for assessing the responses of SC neurons to different combinations of cross-modal and within-modal stimuli of different efficacies.
PMCID: PMC2824893  PMID: 18486113
Within-modal; multisensory; computation; maximum; averaging
16.  Multisensory integration in the superior colliculus requires synergy among cortico-collicular inputs 
Influences from the visual (AEV), auditory (FAES) and somatosensory (SIV) divisions of the cat anterior ectosylvian sulcus (AES) play a critical role in rendering superior colliculus (SC) neurons capable of multisensory integration. However, it is not known whether this is accomplished via their independent sensory-specific action or via some cross-modal cooperative action that emerges as a consequence of their convergence on SC neurons. Using visual-auditory SC neurons as a model, we examined how selective and combined deactivation of FAES and AEV affected SC multisensory (visual-auditory) and unisensory (visual-visual) integration capabilities. As noted earlier, multisensory integration yielded SC responses that were significantly greater than those evoked by the most effective individual component stimulus. This multisensory ‘response enhancement’ was more evident when the component stimuli were weakly effective. Conversely, unisensory integration was dominated by the lack of response enhancement. During cryogenic deactivation of FAES and/or AEV, the unisensory responses of SC neurons were only modestly affected; however, their multisensory response enhancement showed a significant downward shift and was eliminated. The shift was similar in magnitude for deactivation of either AES subregion and, in general, only marginally greater when both were deactivated simultaneously. These data reveal that SC multisensory integration is dependent on the cooperative action of distinct subsets of unisensory corticofugal afferents; afferents whose sensory combination matches the multisensory profile of their midbrain target neurons, and whose functional synergy is specific to rendering SC neurons capable of synthesizing information from those particular senses.
PMCID: PMC2805025  PMID: 19458228
Cross-modal; within-modal; enhancement; deactivation; ectosylvian; unisensory
17.  An Emergent Model of Multisensory Integration in Superior Colliculus Neurons 
Neurons in the cat superior colliculus (SC) integrate information from different senses to enhance their responses to cross-modal stimuli. These multisensory SC neurons receive multiple converging unisensory inputs from many sources; those received from association cortex are critical for the manifestation of multisensory integration. The mechanisms underlying this characteristic property of SC neurons are not completely understood, but can be clarified with the use of mathematical models and computer simulations. Thus the objective of the current effort was to present a plausible model that can explain the main physiological features of multisensory integration based on the current neurological literature regarding the influences received by SC from cortical and subcortical sources. The model assumes the presence of competitive mechanisms between inputs, nonlinearities in NMDA receptor responses, and provides a priori synaptic weights to mimic the normal responses of SC neurons. As a result, it provides a basis for understanding the dependence of multisensory enhancement on an intact association cortex, and simulates the changes in the SC response that occur during NMDA receptor blockade. Finally, it makes testable predictions about why significant response differences are obtained in multisensory SC neurons when they are confronted with pairs of cross-modal and within-modal stimuli. By postulating plausible biological mechanisms to complement those that are already known, the model provides a basis for understanding how SC neurons are capable of engaging in this remarkable process.
PMCID: PMC2861478  PMID: 20431725
visual-acoustic neurons; anterior ectosylvian sulcus; enhancement; suppression; inverse effectiveness principle; neural network modelling
18.  The Differing Impact of Multisensory and Unisensory Integration on Behavior 
Pooling and synthesizing signals across different senses often enhances responses to the event from which they are derived. Here we examine whether multisensory response enhancements are attributable to a redundant target effect (two stimuli rather than one), or if there is some special quality inherent in the combination of cues from different senses. To test these possibilities, the performance of animals in localizing and detecting spatiotemporally concordant visual and auditory stimuli was examined when these stimuli were presented individually (visual or auditory), or in cross-modal (visual-auditory) and within-modal (visual-visual, auditory-auditory) combinations. Performance enhancements proved to be far greater for combinations of cross-modal than within-modal stimuli and support the idea that the behavioral products derived from multisensory integration are not attributable to simple target redundancy. One likely explanation is that while cross-modal signals offer statistically independent samples of the environment, within-modal signals can exhibit substantial covariance, and consequently multisensory integration can yield more substantial error reduction than unisensory integration.
PMCID: PMC2678542  PMID: 19369558
Multisensory Integration; Unisensory Integration; Multimodal; Vision; Audition; Cross-modal
19.  Postnatal Experiences Influence How the Brain Integrates Information from Different Senses 
Sensory processing disorder (SPD) is characterized by anomalous reactions to, and integration of, sensory cues. Although the underlying etiology of SPD is unknown, one brain region likely to reflect these sensory and behavioral anomalies is the superior colliculus (SC), a structure involved in the synthesis of information from multiple sensory modalities and the control of overt orientation responses. In the present review we describe normal functional properties of this structure, the manner in which its individual neurons integrate cues from different senses, and the overt SC-mediated behaviors that are believed to manifest this “multisensory integration.” Of particular interest here is how SC neurons develop their capacity to engage in multisensory integration during early postnatal life as a consequence of early sensory experience, and the intimate communication between cortex and the midbrain that makes this developmental process possible.
PMCID: PMC2762369  PMID: 19838323
multisensory; integration; plasticity; sensory processing disorder; superior colliculus
20.  Temporal Profiles of Response Enhancement in Multisensory Integration 
Frontiers in Neuroscience  2008;2(2):218-224.
Animals have evolved multiple senses that transduce different forms of energy as a way of increasing their sensitivity to environmental events. Each sense provides a unique and independent perspective on the world, and very often a single event stimulates several of them. In order to make best use of the available information, the brain has also evolved the capacity to integrate information across the senses (“multisensory integration”). This facilitates the detection, localization, and identification of a given event, and has obvious survival value for the individual and the species. Multisensory responses in the superior colliculus (SC) evidence shorter latencies and are more robust at their onset. This is the phenomenon of initial response enhancement in multisensory integration, which is believed to represent a real time fusion of information across the senses. The present paper reviews two recent reports describing how the timing and robustness of sensory responses change as a consequence of multisensory integration in the model system of the SC.
PMCID: PMC2622754  PMID: 19225595
multisensory; cross-modal; superior colliculus; enhancement; latency
21.  Multisensory Integration Produces an Initial Response Enhancement 
The brain has evolved the ability to integrate information across the senses in order to improve the detection and disambiguation of biologically significant events. This multisensory synthesis of information leads to faster (and more accurate) behavioral responses, yet the underlying neural mechanisms by which these responses are speeded are as yet unclear. The aim of these experiments was to evaluate the temporal properties of multisensory enhancement in the physiological responses of neurons in the superior colliculus (SC). Of specific interest was the temporal evolution of their responses to individual modality-specific stimuli as well as to cross-modal combinations of these stimuli. The results demonstrate that cross-modal stimuli typically elicit faster, more robust, and more reliable physiological responses than do their modality-specific component stimuli. Response measures sensitive to the time domain showed that these multisensory responses were enhanced from their very onset, and that the acceleration of the enhancement was greatest within the first 40ms (or 50% of the response). The latter half of the multisensory response was typically only as robust and informative as predicted by a linear combination of the unisensory component responses. These results may reveal some of the key physiological changes underlying many of the SC-mediated behavioral benefits of multisensory integration.
PMCID: PMC2526011  PMID: 18958232
multisensory; superior colliculus; physiology; cross-modal; information; latency
22.  Direct and Indirect Regulation of Cytokine and Cell Cycle Proteins by EBNA-2 during Epstein-Barr Virus Infection 
Journal of Virology  2001;75(8):3537-3546.
We have studied the pathways of regulation of cytokine and cell cycle control proteins during infection of human B lymphocytes by Epstein-Barr virus (EBV). Among 30 cytokine RNAs analyzed by the RNase protection assay, tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor, lymphotoxin (LT), and LTβ were found to be regulated within 20 h of EBV infection of primary B cells. Similar results were obtained using the estrogen-regulated EBNA-2 cell line EREB2.5, in which RNAs for LT and TNF-α were induced within 6 h of activation of EBNA-2. Expression of Notch also caused an induction of TNF-α RNA. The induction of TNF-α RNA by EBNA-2 was indirect, and constitutive expression of either LMP-1 or c-myc proteins did not substitute for EBNA-2 in induction of TNF-α RNA. Cyclin D2 is also an indirect target of EBNA-2-mediated transactivation. EBNA-2 was found to activate the cyclin D2 promoter in a transient-transfection assay. A mutant of EBNA-2 that does not bind RBP-Jκ retained some activity in this assay, and activation did not depend on the presence of B-cell-specific factors. Deletion analysis of the cyclin D2 promoter revealed that removal of sequences containing E-box c-myc consensus DNA binding sequences did not reduce EBNA-2-mediated activation of the cyclin D2 promoter in the transient-transfection assay. The results indicate that cytokines are an early target of EBNA-2 and that EBNA-2 can regulate cyclin D2 transcription in EBV-infected cells by mechanisms additional to the c-myc pathway.
PMCID: PMC114845  PMID: 11264343

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