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Targeting G1 cyclins in cancer chemoprevention.

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Call No.	RC268.15 .M3 2005
Author	Ma, Yan, 1972-
Title	Targeting G1 cyclins in cancer chemoprevention.
Date	2005
Abstract	Retinoids, natural and synthetic derivatives of vitamin A, are active in cancer treatment and chemoprevention. There is a need for an in-depth understanding of the mechanisms that account for retinoid response or resistance in lung cancer prevention. G1 cyclins (D-type cyclins and E-type cyclins) promote G1/S progression and are aberrantly expressed in cancer. We reported previously that all- trans -retinoic acid (RA) chemoprevented carcinogenic transformation of human bronchial epithelial (HBE) cells through proteasomal degradation of G1 cyclins (cyclin D1 and cyclin E). RA is shown in this thesis to activate distinct mechanisms to regulate different D-type cyclins in HBE cells. Glycogen synthesis kinase 3 (GSK3) is critical for RA regulation of cyclin D1 but not cyclin D3. Expression of cyclin D1 and cyclin D3 was deregulated in RA-resistant HBE cells, directly implicating these species in RA response. D-type cyclins were independently targeted using siRNAs. Repression of each D-type cyclin expression independently suppressed HBE growth. Repression of all D-type cyclins cooperatively suppressed HBE growth. The role of cyclin E in lung carcinogenesis was explored in vitro and in vivo. Overexpression of cyclin E promoted anchorage-independent growth of mouse lung epithelial cells. Mice constitutively overexpressing wild-type or degradation-resistant mutant cyclin E in the lung under the control of human surfactant protein C (SP-C) promoter developed respiratory epithelium premaligancy and malignancy and showed evidence of local metastasis. The siRNA targeting of each E-type cyclin suppressed HBE cell growth. A synthetic triterponoid, 2-cyano-3,12-dioxooleana-1,9-then-28-oic acid (CDDO), was found to repress effectively exogenous cyclin E expression. Microarray analysis uncovered 11 candidate RA-target genes including 3 novel species. RA dysregulated the expression of several species in RA-resistant HBE cells, indicating these were directly implicated in RA signaling. Taken together, these studies highlight G1 cyclins as molecular pharmacological targets for cancer chemoprevention. Future studies will further understand the signaling pathway involved in RA regulation of G1 cyclins. The features of wild-type or mutant cyclin E transgenic species in lung carcinogenesis will each be explored further. The studies in this thesis also provide a strong rationale for use of G1 cyclin targeting agents to treat or chemoprevent lung cancers.
Description	1 online resource (xviii, 172 leaves) : illustrations (some color)
Format	application/pdf
Advisor	Dmitrovsky, Ethan
Subject	Bronchi -- Cancer -- Chemoprevention. ; Cyclins. ; Retinoids -- Therapeutic use. ; Cellular control mechanisms. ; G1 Phase.
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.3243

Title	ma2005 1
Full Text	Targeting G1 Cyclins in Cancer 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 Yan Ma DARTMOUTH COLLEGE Hanover, New Hampshire June 2, 2005

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Targeting G1 cyclins in cancer chemoprevention.

Targeting G1 cyclins in cancer chemoprevention.