Identification of GAPDH as a protein target of the saframycin antiproliferative agents

Chengguo Xing, Jacob R. LaPorte, Joseph K. Barbay, Andrew G. Myers

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Saframycin A (SafA) is a member of a class of natural products with potent antiproliferative effects in leukemia- and tumor-derived cells. This activity is frequently conjectured to derive from the ability of saframycins to covalently modify duplex DNA. We used a DNA-linked affinity purification technique to identify GAPDH as a protein target of DNA-small molecule adducts of several members of the saframycin class. Nuclear translocation of GAPDH occurs upon treatment of cancer cells with saframycins, and depletion of cellular GAPDH levels by small interfering RNA transfection confers drug resistance. Roeder and coworkers have recently suggested that GAPDH is a key transcriptional coactivator necessary for entry into S phase. Our data suggest that GAPDH is also capable of forming a ternary complex with saframycin-related compounds and DNA that induces a toxic response in cells. These studies implicate a previously unknown molecular mechanism of antiproliferative activity and, given that one member of the saframycin class has shown efficacy in cancer treatment, suggest that GAPDH may be a potential target for chemotherapeutic intervention.

Original languageEnglish (US)
Pages (from-to)5862-5866
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number16
DOIs
StatePublished - Apr 20 2004

Fingerprint Dive into the research topics of 'Identification of GAPDH as a protein target of the saframycin antiproliferative agents'. Together they form a unique fingerprint.

Cite this