Abstract/Details

Targeting Akt in breast cancer: Studies using transgenic mice and inhibitory peptides


2003 2003

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Abstract (summary)

Akt is serine/threonine kinase which regulates multiple pathways in cells including apoptosis, cell division and homeostasis. These functions can be co-opted by cancer cells to allow for progression of the disease. To study the effects of Akt1 overexpression on the initiation of breast cancer, we generated transgenic mice which have targeted expression of human cAkt1 in mammary epithelial cells. While no evidence of tumor formation was found, mammary glands of transgenic mice were slow to involute following cessation of nursing, and some hyperplasia was present. Further analysis suggested a role for cyclin D1 in the inhibition of involution seen in transgenic mice.

The AH domain of Akt, comprising the first approximately 150 amino acids of the kinase, has been suggested to be a homodimerization domain. We used PCR to generate the AH domain of Akt1 and Akt2, and tested their ability to inhibit the Akt pathway. Both domains were effective at sensitizing U87 cells to camptothecin, and caused some basal apoptosis in several breast and prostate cancer cell lines. These peptides appear to be working via an Akt dependent mechanism, based on assays measuring AFX transcriptional activity. The mechanism of action of these peptides appears to be inhibition of activation loop phosphorylation by binding to Akt and either directly or indirectly blocking PDK1 activation of the kinase. These results suggest that the AH domain of Akt may be a favorable target for small molecule drug design.

Indexing (details)


Subject
Pharmacology;
Oncology;
Cellular biology
Classification
0419: Pharmacology
0992: Oncology
0379: Cellular biology
Identifier / keyword
Health and environmental sciences; Biological sciences; Akt; Breast cancer; Inhibitory peptides; Transgenic
Title
Targeting Akt in breast cancer: Studies using transgenic mice and inhibitory peptides
Author
Ackler, Scott
Number of pages
129
Publication year
2003
Degree date
2003
School code
0544
Source
DAI-B 65/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780496077304, 0496077309
Advisor
Glazer, Robert I.
University/institution
Georgetown University Medical Center
University location
United States -- District of Columbia
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3147503
ProQuest document ID
305269904
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/305269904/abstract
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