The clinical course of some macroadenomas and all pituitary microadenomas is characterized by transient rather than continual abnormal growth. As the activation of a classical proto-oncogene would be expected to lead to a persistent rather than transient increase in mitotic/apoptotic ratio, it is perhaps not surprising that few candidate genes have been convincingly implicated in pituitary tumour formation. A pathogenic mechanism capable of temporarily rather than permanently uncoupling the tight co-regulation and co-dependence of mitosis and apoptosis would more closely fit the observed trophic behaviour of most pituitary adenomas. A pro-apoptotic heterotrimeric complex containing the evolutionarily-conserved products of the hSav1, Mst2 and Lats1/2 genes has recently been implicated in a signal transduction pathway involved in the co-regulation of mitosis and apoptosis. In the current study we have demonstrated that down-regulation of one or more of these genes in the pituitary-derived alphaT4 cell line by transfection with a mixture of antisense phosphorothioate oligonucleotides complementary to all three genes, results in an increase in total cell numbers when compared with controls at both 24h and 48h after transfection. When the same mixture of antisense oligonucleotides with bromodeoxyuridine (BrdU) as a marker of cell proliferation was infused directly into the region of the pituitary of free-living, young, male Wistar rats for 4 days, the mitotic index quantified directly in thin anterior pituitary tissue sections was increased between 2- and 3-fold in 4 of the 6 pituitary glands examined compared to that measured in pituitary glands infused with BrdU alone (0.298 ± 0.045% v. 0.1 ± 0.016%). These preliminary data suggest that a transient change in the activity of multiple genes associated with the normally tight coupling of mitosis to apoptosis¬ can result in a measurable increase in mitotic activity in the anterior pituitary. It is possible that transient down-regulation of one or more of these genes could result in the generation of a surfeit of entirely normal cells that would persist once hSav1, Mst2 and Lats1/2 gene equilibrium is restored.
|Translated title of the contribution||Transient Uncoupling of Mitotic and Apoptotic Co-regulation in the Normal Male Rat Pituitary: a Potential Model of Pituitary Microadenoma Formation|
|Title of host publication||Association of Physicians of Great Britain and Ireland|
|Number of pages||1|
|Publication status||Published - 2007|
Bibliographical noteName and Venue of Event: Association of Physicians annual meeting
Conference Proceedings/Title of Journal: Quarterly Journal of Medicine
Conference Organiser: Association of Physicians