Biomedical subjects

Matthew P Pando

Publications and source records attributed to Matthew P Pando.

6 recordsLinked to original sources

PubMed2006

Alternative isoform discrimination by the next generation of expression profiling microarrays.

Microarray expression profiling has revolutionised the way that many therapeutic targets have been identified over the past 10 years. High-density microarrays have allowed scientists to simultaneously scrutinise the expression of all genes encoded on a given genome. Although the data collected from classically designed microarrays greatly enriched the pool of information available to help guide the selection and design of new therapeutic strategies, they were unable to tell the complete story. The major limitation with most array designs is that they can only produce a global expression value for all transcripts produced from a specific locus and cannot monitor each individual alternative isoform produced from the interrogated locus. Recently, new array designs have been described, and become commercially available, that can efficiently monitor individual alternatively spliced isoforms produced from a single locus, allowing the research community to get a more accurate picture of the biological landscape of the expressed transcripts.

Alternative Splicing↗

PubMed2003

On the communication pathways between the central pacemaker and peripheral oscillators.

Circadian rhythms are regulated by clocks located in specific structures of the CNS, such as the suprachiasmatic nucleus (SCN) in mammals, and by peripheral oscillators present in various other tissues. The expression of essential clock genes oscillates both in the SCN and in peripheral pacemakers. Peripheral tissues in the fly and in the fish are directly photoreceptive. In particular, we have established the Z3 embryonic zebrafish cell line that recapitulates the dynamic light-dependent regulation of the vertebrate clock in vitro. In mammals the synchronization to daily light cycles involves neural connections from a subset of light-sensitive receptor-containing retinal ganglion cells. Humoral and/or hormonal signals originating from the SCN are thought to provide timing cues to peripheral clocks. However, alternative routes exist, as some peripheral clocks in mammals can be specifically entrained in a SCN-independent manner by restricted feeding regimes. Thus, not all peripheral tissues are equal in circadian rhythmicity. Testis, for example, displays no intrinsic circadian rhythmicity and the molecular mechanisms of clock gene activation in male germ cells appear to differ from other tissues. The study of the connecting routes that link the SCN to peripheral tissues is likely to reveal signalling pathways of fundamental physiological significance.

Animals↗

PubMed2002

Phenotypic rescue of a peripheral clock genetic defect via SCN hierarchical dominance.

The mammalian circadian system contains both central and peripheral oscillators. To understand the communication pathways between them, we have studied the rhythmic behavior of mouse embryo fibroblasts (MEFs) surgically implanted in mice of different genotypes. MEFs from Per1(-/-) mice have a much shorter period in culture than do tissues in the intact animal. When implanted back into mice, however, the Per1(-/-) MEF take on the rhythmic characteristics of the host. A functioning clock is required for oscillations in the target tissues, as arrhythmic clock(c/c) MEFs remain arrhythmic in implants. These results demonstrate that SCN hierarchical dominance can compensate for severe intrinsic genetic defects in peripheral clocks, but cannot induce rhythmicity in clock-defective tissues.

Animals↗

PubMed2002

Light induction of a vertebrate clock gene involves signaling through blue-light receptors and MAP kinases.

The signaling pathways that couple light photoreception to entrainment of the circadian clock have yet to be deciphered. Two prominent groups of candidates for the circadian photoreceptors are opsins (e.g., melanopsin) and blue-light photoreceptors (e.g., cryptochromes). We have previously showed that the zebrafish is an ideal model organism in which to study circadian regulation and light response in peripheral tissues. Here, we used the light-responsive zebrafish cell line Z3 to dissect the response of the clock gene zPer2 to light. We show that the MAPK (mitogen-activated protein kinase) pathway is essential for this response, although other signaling pathways may also play a role. Moreover, action spectrum analyses of zPer2 transcriptional response to monochromatic light demonstrate the involvement of a blue-light photoreceptor. The Cry1b and Cry3 cryptochromes constitute attractive candidates as photoreceptors in this setting. Our results establish a link between blue-light photoreceptors, probably cryptochromes, and the MAPK pathway to elicit light-induced transcriptional activation of clock genes.

Adaptation, Ocular↗

PubMed2002

Unraveling the mechanisms of the vertebrate circadian clock: zebrafish may light the way.

Most organisms display oscillations of approximately 24 hours in their physiology. In higher organisms, these circadian oscillations in biochemical and physiological processes ultimately control complex behavioral rhythms that allow an organism to thrive in its natural habitat. Daily and seasonal light cycles are mainly responsible for keeping the circadian system properly aligned with the environment. The molecular mechanisms responsible for the control of the circadian clock have been explored in a number of systems. Interestingly, the circadian oscillations that are responsive to environmental stimuli are present very early during development. This review focuses on the advantages of using the zebrafish to study the development of the vertebrate circadian system and light-dependent signaling to the clock.

Animals↗

PubMed2002

Fanconi anemia protein complex is a novel target of the IKK signalsome.

Fanconi anemia (FA), a genetic disorder predisposing to aplastic anemia and cancer, is characterized by hypersensitivity to DNA-damaging agents and oxidative stress. Five of the cloned FA proteins (FANCA, FANCC, FANCE, FANCF, FANCG) appear to be involved in a common functional pathway that is required for the monoubiquitination of a sixth gene product, FANCD2. Here, we report that FANCA associates with the IkappaB kinase (IKK) signalsome via interaction with IKK2. Components of the FANCA complex undergo rapid, stimulus-dependent changes in phosphorylation, which are blocked by kinase-inactive IKK2 (IKK2 K > M). When exposed to mitomycin C, cells expressing IKK2 K > M develop a cell cycle abnormality characteristic of FA. Thus, FANCA may function to recruit IKK2, thus providing the cell a means of rapidly responding to stress.

Adenoviridae↗