Snf1/AMPK-related kinase Hunk is required for colorectal tumorigenesis and inhibits Pml-mediated suppression of Akt following DNA damage / Jason Ju Hyung Jung.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Jung, Jason Ju Hyung.

Contributor:

Chodosh, Lewis, advisor.

Lynch, John P., committee member.

Assoian, Richard K., committee member.

Kissil, Joseph L., committee member.

University of Pennsylvania. Cell and Molecular Biology.

Language:

English

Subjects (All):

Penn dissertations--Cell and Molecular Biology.

Cell and Molecular Biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and Molecular Biology.

Cell and Molecular Biology--Penn dissertations.

Physical Description:

viii, 149 pages : color illustrations ; 29 cm

Production:

2013.

Summary:

Despite recent advances that have led to improved survival rates, colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality among both men and women in the United States. As such, elucidation of the molecular events that occur during progression of normal colon crypt cells into CRC is vital to the development of new therapeutic strategies against this disease. This dissertation addresses the role of the serine/threonine kinase Hunk (Hormonally Upregulated Neu-tumor associated Kinase) in the process of colorectal tumorigenesis.

We have previously demonstrated that Hunk is overexpressed in several human cancers, including colon and breast cancers, and subsequently identified a requirement for Hunk in mammary primary tumorigenesis as well as mammary tumor metastasis to the lung. We now report that the survival of colon crypt epithelial cells following DNA damage induced by exposure to chemical carcinogens or gamma-irradiation requires the Snf1/AMPK-related kinase, Hunk. Accordingly, germline deletion of Hunk in mice impaired crypt epithelial cell survival as well as colorectal tumorigenesis following exposure to the DNA damage-inducing carcinogen azoxymethane. Consistent with this, Hunk knockdown in human colon cancer cells harboring endogenous DNA damage induced apoptosis and impaired tumor growth in immunocompromised mice. The apoptotic response to DNA damage observed in Hunk-deficient cells following exposure to gamma-irradiation, azoxymethane or the chemotherapeutic agent Adriamycin resulted from a requirement for Hunk in DNA damage-induced Akt activation. Specifically, we have found that Hunk binds and co-localizes with the tumor suppressor Pml, and that Pml knockdown in cells exposed to DNA damaging agents rescues the defects in Akt activation and cell survival induced by loss of Hunk. Taken together, our findings indicate that Hunk promotes the survival of cells exposed to DNA damage by inhibiting Pml-mediated suppression of Akt activation, and identify a pro-survival role for Hunk during genotoxic stress that is required for colorectal tumorigenesis.

Notes:

Adviser: Lewis Chodosh.

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2013.

Includes bibliographical references.

OCLC:

862507720