Find results with:

Add another field

Search by date

to

Searching collections:

Dartmouth Dissertations

Add or remove collections

Home Dartmouth Dissertations Page 1

Reference URL

To link to the entire object, paste this link in email, IM or document

To embed the entire object, paste this HTML in website

To link to this page, paste this link in email, IM or document

To embed this page, paste this HTML in website

The novel p53 target gene STK17A : implications for cancer therapy / by Pingping Mao

you wish to report:

Your comment:

Your Name:

Submit

Cancel

...

Back to top

Powered by CONTENTdm®

Author	Mao, Pingping
Title	The novel p53 target gene STK17A : implications for cancer therapy / by Pingping Mao
Date	2014
Abstract	Testicular germ cell tumors (TGCTs) are highly curable with cisplatin-based therapy. The p53 tumor suppressor is induced in response to a variety of cellular stresses. Our previous work has implicated an important role for p53 in TGCT hypersensitivity to cisplatin. Identifying novel p53 target genes in response to genotoxic stress in TGCTs may reveal critical modulators of cytotoxic responses and aid in developing new chemotherapeutic strategies. The work presented here demonstrates that STK17A is a bona-fide p53 target gene. In testicular cancer-derived embryonal carcinoma (EC) NT2/D1 cells, STK17A is induced by a variety of DNA damaging agents including cisplatin in a p53-dependent manner. STK17A is a transcriptional target of p53 and modulates cisplatin toxicity and reactive oxygen species (ROS) generation in EC cells. Knockdown of STK17A confers resistance to cisplatin-induced growth suppression and apoptotic cell death associated with decreased ROS levels. These findings advance our understanding of TGCT hypersensitivity to cytotoxic drugs by revealing STK17A as a modulator of p53-mediated chemotherapy response. STK17A is a largely uncharacterized serine/threonine kinase. Unexpectedly, in silico analysis indicates that STK17A is highly overexpressed in glioma patients in a tumor grade-dependent manner with the highest levels in glioblastoma (GBM). Furthermore, high STK17A expression correlates with poor clinical outcome and decreased survival of glioma patients. This correlation is independent of age, molecular phenotype, IDH1 mutation, PTEN loss, and alterations in the p53 pathway. Knockdown of STK17A in GBM cells results in decreased cell proliferation, clonogenicity, anchorage-independent colony formation and a dramatic alteration in cell shape that is associated with impaired cell migration and invasion. STK17A knockdown also sensitizes GBM cells to genotoxic stress. We demonstrate that STK17A provides a proliferative and survival advantage to GBM cells. Finally, we examined the potency and efficacy of several candidate kinase inhibitors of STK17A, among which A48 and A49 suppress STK17A kinase activity and inhibit GBM cell proliferation and clonogenicity. Future efforts are needed to further examine potency, specificity and toxicity of agents which pharmacologically target STK17A in GBM. Taken together, we identified that STK17A is a direct target gene of p53 that participates in TGCT hypersensitivity to cisplatin. In addition, our findings implicate an important role for STK17A in GBM survival and progression, suggesting that STK17A may be a novel therapeutic target to be exploited for GBM treatment.
Description	1 online resource (xvi, 196 leaves) : illustrations (mostly color)
Format	application/pdf
College	Geisel School of Medicine at Dartmouth -- Experimental and Molecular Medicine Program.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1927

Find results with:

Searching collections:

Home Dartmouth Dissertations Page 1

The novel p53 target gene STK17A : implications for cancer therapy / by Pingping Mao

Object Description

Description

The novel p53 target gene STK17A : implications for cancer...

The novel p53 target gene STK17A : implications for cancer...

	All
	Pages Enter page numbers or page ranges separated by commas. For example: 1,3,5-12