Diminished drug transport and augmented radiation sensitivity caused by loss of RLIP76

FEBS Lett. 2008 Oct 15;582(23-24):3408-14. doi: 10.1016/j.febslet.2008.09.001. Epub 2008 Sep 18.


This study was undertaken to characterize the consequences of Ral-interacting protein (RLIP76)-loss with respect to drug resistance, transport, radiation resistance, and alternative transport mechanisms in mouse embryonic fibroblasts (MEFs). MEFs were derived from RLIP76+/+, RLIP76+/- and RLIP76-/- mice. The transport of doxorubicin (DOX), colchicine (COL), leukotriene C4 and dinitrophenyl S-glutathione (DNP-SG) was analyzed in inside-out vesicles (IOVs) prepared from MEFs. We used immuno-titration of transport activity to determine the contribution of RLIP76, MRP1, and p-glycoprotein (Pgp) towards total transport activity. Loss of RLIP76 alleles resulted in significant sensitization to radiation, DOX, cisplatin, and vinorelbine (VRL). In IOVs prepared from MEFs, we observed a stepwise loss of transport activity. Loss of RLIP76 confers sensitivity to xenobiotics and radiation due to the loss of a common transport mechanism for glutathione-electrophile conjugates and xenobiotics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / metabolism
  • Alkylating Agents / toxicity
  • Animals
  • Anthracyclines / metabolism
  • Anthracyclines / toxicity
  • Biological Transport / genetics
  • Doxorubicin / metabolism
  • Doxorubicin / toxicity
  • Drug Resistance, Neoplasm* / genetics
  • Endocytosis* / genetics
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Insulin / metabolism
  • Mice
  • Mice, Mutant Strains
  • Oxidative Stress
  • Quantum Dots
  • Radiation Tolerance* / genetics
  • Rhodamines / metabolism
  • Xenobiotics / metabolism*
  • Xenobiotics / toxicity


  • Alkylating Agents
  • Anthracyclines
  • GTPase-Activating Proteins
  • Insulin
  • Ralbp1 protein, mouse
  • Rhodamines
  • Xenobiotics
  • Doxorubicin