| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on June 28, 2006
Accepted on July 14, 2006
Department of Medicine, Mount Sinai Hospital and University of Toronto, Department of Pathology, University Health Network and University of Toronto; The Freeman Centre for Endocrine Oncology and The Ontario Cancer Institute, 610 University Avenue #8-327, Toronto, Ontario, Canada M5G-2M9
* To whom correspondence should be addressed. E-mail: sylvia.asa{at}uhn.on.ca.
We reported the expression of the lymphoid zinc finger transcription factor Ikaros (Ik) in the endocrine pituitary gland where the usual isoforms, Ik1 and Ik2, are thought to play multiple physiological roles. The gene is alternatively spliced to yield a dominant negative isoform, Ik6, in nearly half of human pituitary tumors. We show here that the tumor-specific truncated Ik6 isoform promotes pituitary tumor AtT20 corticotroph and GH4 mammosomatotroph cell growth evidenced by increased S-phase entry, colony formation in soft agar, and growth of xenografts in vivo. Ik6-mediated cell growth was associated with enhanced protection against apoptosis and up-regulation of the anti-apoptotic factor Bcl-XL but not the related Bcl-2 family member. The effect of Ik6 on Bcl-XL induction was not reproduced by siRNA-mediated Ik-down-regulation, indicating that this effect is not mediated entirely by disruption of Ik1 action. In co-transfection studies, Ik1 attenuated and Ik6 enhanced Bcl-XL promoter activity. The effect of Ik6 was mimicked by histone deacetylation inhibition but not by methylation inhibition. Further, chromatin immunoprecipitation confirmed the ability of Ik6 to selectively acetylate histone 3 sites but not influence methylation of the Bcl-XL promoter. Thus, the contribution of Ik6 to tumor pathogenesis involves up-regulation of an anti-apoptotic signal generated through selective acetylation of the Bcl-XL promoter.
This article has been cited by other articles:
 |
|
 |
|
  S. Ezzat and S. L Asa The emerging role of the Ikaros stem cell factor in the neuroendocrine system J. Mol. Endocrinol., August 1, 2008; 41(2): 45 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Loeper, S. L. Asa, and S. Ezzat Ikaros Modulates Cholesterol Uptake: A Link between Tumor Suppression and Differentiation Cancer Res., May 15, 2008; 68(10): 3715 - 3723. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, S. L. Asa, and S. Ezzat Ikaros Is Regulated through Multiple Histone Modifications and Deoxyribonucleic Acid Methylation in the Pituitary Mol. Endocrinol., May 1, 2007; 21(5): 1205 - 1215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, K. Lee, S. L. Asa, and S. Ezzat Epigenetic Silencing through DNA and Histone Methylation of Fibroblast Growth Factor Receptor 2 in Neoplastic Pituitary Cells Am. J. Pathol., May 1, 2007; 170(5): 1618 - 1628. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
