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Post-translational modification in retinoid action: a role for UBEIL in cancer therapy and chemoprevention.

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Call No.	RC271.B53 P58 2004
Author	Pitha-Rowe, Ian F.
Title	Post-translational modification in retinoid action: a role for UBEIL in cancer therapy and chemoprevention.
Date	2004
Abstract	The retinoids--natural and synthetic derivatives of vitamin A--are active in cancer therapy and chemoprevention. The signals that underlie retinoid clinical activity are triggered by induction of retinoid target genes. Therefore, a greater understanding of the mechanisms of retinoid clinical activity can be gained through in-depth examinations of individual target genes. This thesis examines UBE1L , a retinoid target gene in acute promyelocytic leukemia (APL) differentiation therapy and lung cancer chemoprevention. UBE1L mRNA and protein expression was induced by all- trans -retinoic acid (RA) treatment of retinoid sensitive but not resistant NB4 APL cells. In luciferase-based reporter assays, the UBE1L promoter was activated by RA treatment. Promoter activity was enhanced by co-transfection of retinoid receptors and repressed by PML/RARα. Ectopic expression of UBE1L caused apoptosis in APL cells and repressed PML/RAR_ levels. UBE1L is the activating enzyme for the ubiquitin-like modifier interferon (IFN)-stimulated gene, 15 kDa (ISG15). ISG15 expression and conjugation were induced by RA treatment of NB4 APL cells. Knock-down of UBE1L expression using inhibitory RNA reduced IFN- and RA-induced ISG15 conjugation. Ectopic UBE1L expression enhanced ISG15 conjugation. Co-transfection of an ISG15 deconjugating enzyme, UBP43, inhibited UBEIL-mediated PML/RARα repression. To uncover retinoid target genes in lung cancer chemoprevention, microarray analyses were performed on a cellular model of RA-mediated lung cancer chemoprevention. UBE1L was induced in this model after prolonged RA treatment. Immunohistological analyses revealed UBE1L expression in histologically normal human bronchial epithelium whereas cyclin D1 levels were reduced. Co-transfection of UBE1L repressed cyclin D1 expression linking UBE1L expression to an RA-mediated effect in lung cancer chemoprevention. UBP43 inhibited this repression. In addition, immunoblot analyses revealed repressed UBE1L expression in lung cancers versus paired normal tissue from the same case. These studies revealed that UBE1L is an RA target gene in APL differentiation therapy and lung cancer chemoprevention. UBE1L was implicated in repression of PML/RAR_ and cyclin D1 levels. A strong rationale was provided for further investigations into the role of ISG15 conjugation in RA-mediated effects and the biological significance of ISG15 conjugation. Future work should focus on exploring the potential of targeting the ISG15 conjugation pathway in cancer therapy or chemoprevention.
Description	1 online resource (xx, 168 leaves) : illustrations (some color)
Format	application/pdf
Advisor	Dmitrovsky, Ethan
Subject	Retinoids -- Mechanism of action. ; Post-translational modification. ; Tretinoin -- Therapeutic use. ; Lungs -- Cancer -- Chemoprevention.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org/10.1349/ddlp.3327

Title	pitha-rowe2004 1
Full Text	Post-Translational Modification in Retinoid Action: A Role for UBE1L in Cancer Therapy and Chemoprevention A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Ian F. Pitha-Rowe DARTMOUTH COLLEGE Hanover, New Hampshire May 18, 2004

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Post-translational modification in retinoid action: a role for UBEIL in cancer therapy and chemoprevention.

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