HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/3/C1204    most recent 00451.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Zahedi, K. Articles by Soleimani, M. Search for Related Content PubMed PubMed Citation Articles by Zahedi, K. Articles by Soleimani, M.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

Spermidine/spermine N¹-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G₂ arrest

¹Division of Nephrology and Hypertension, Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; ²Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; ³Roswell Park Cancer Institute, Buffalo, New York; and ⁴Department of Veterans Affairs Medical Center, Cincinnati, Ohio

Submitted 23 August 2006 ; accepted in final form 18 October 2006

Expression of spermidine/spermine N¹-acetyltransferase (SSAT) increases in kidneys subjected to ischemia-reperfusion injury (IRI). Increased expression of SSAT in vitro leads to alterations in cellular polyamine content, depletion of cofactors and precursors of polyamine synthesis, and reduced cell proliferation. In our model system, a >28-fold increase in SSAT levels in HEK-293 cells leads to depletion of polyamines and elevation in the enzymatic activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase, suggestive of a compensatory reaction to increased polyamine catabolism. Increased expression of SSAT also led to DNA damage and G₂ arrest. The increased DNA damage was primarily due to the depletion of polyamines. Other factors such as increased production of H₂O₂ due to polyamine oxidase activity may play a secondary role in the induction of DNA lesions. In response to DNA damage the ATM/ATR Chk1/2 DNA repair and cell cycle checkpoint pathways were activated, mediating the G₂ arrest in SSAT-expressing cells. In addition, the activation of ERK1 and ERK2, which play integral roles in the G₂/M transition, is impaired in cells expressing SSAT. These results indicate that the disruption of polyamine homeostasis due to enhanced SSAT activity leads to DNA damage and reduced cell proliferation via activation of DNA repair and cell cycle checkpoint and disruption of Raf MEK ERK pathways. We propose that in kidneys subjected to IRI, one mechanism through which increased expression of SSAT may cause cellular injury and organ damage is through induction of DNA damage and the disruption of cell cycle.

ischemia-reperfusion injury; polyamine depletion; cell proliferation; DNA repair; cell cycle arrest

This article has been cited by other articles:

				A. E. Pegg Spermidine/spermine-N1-acetyltransferase: a key metabolic regulator Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E995 - E1010. [Abstract] [Full Text] [PDF]

				G. Wei, K. DeFeo, C. S. Hayes, P. M. Woster, L. Mandik-Nayak, and S. K. Gilmour Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated-DNA Damage Signaling in Normal Keratinocytes Cancer Res., April 1, 2008; 68(7): 2214 - 2222. [Abstract] [Full Text] [PDF]