Interleukin-15 enhances proteasomal degradation of Bid In normal lymphocytes: implications for Large granular lymphocyte leukemias

Deborah L. Hodge, Jun Yang, Matthew D. Buschman, Paul M. Schaughency, Hong Dang, William Bere, Yili Yang, Ram Savan, Jeff J. Subleski, Xiao-Ming Yin, Thomas P. Loughran, Howard A. Young

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Large granular lymphocyte (LGL) leukemia is a clonal proliferative disease of T and natural killer (NK) cells. Interleukin (IL)-15is important for the development and progression of LGL leukemia and is a survival factor for normal NK and T memory cells. IL-15alters expression of Bcl-2 family members, Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1;however, effects on Bid have not been shown. Using an adoptive transfer model, we show that NK cells from Biddeficient mice survive longer than cells from wild-type control mice when transferred into IL-15-null mice. In normal human NK cells, IL-15significantly reduces Bid accumulation. Decreases in Bid are not due to alterations in RNA accumulation but result from increased proteasomal degradation. IL-15up-regulates the E3 ligase HDM2 and we find that HDM2 directly interacts with Bid. HDM2 suppression by short hairpin RNA increases Bid accumulation lending further support for HDM2 involvement in Bid degradation. In primary leukemic LGLs, Bid levels are low but are reversed with bortezomib treatment with subsequent increases in LGL apoptosis. Overall, these data provide a novel molecular mechanism for IL-15control of Bid that potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid and offers the possibility that proteasome inhibitors may aid in the treatment of LGL leukemia.

Original languageEnglish (US)
Pages (from-to)3986-3994
Number of pages9
JournalCancer Research
Volume69
Issue number9
DOIs
StatePublished - May 1 2009
Externally publishedYes

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Large Granular Lymphocytic Leukemia
Interleukin-15
Interleukins
Lymphocytes
Natural Killer T-Cells
Natural Killer Cells
Noxae
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Adoptive Transfer
Proteasome Endopeptidase Complex
Small Interfering RNA
RNA
Apoptosis
Cytokines
Survival
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hodge, D. L., Yang, J., Buschman, M. D., Schaughency, P. M., Dang, H., Bere, W., ... Young, H. A. (2009). Interleukin-15 enhances proteasomal degradation of Bid In normal lymphocytes: implications for Large granular lymphocyte leukemias. Cancer Research, 69(9), 3986-3994. https://doi.org/10.1158/0008-5472.CAN-08-3735

Interleukin-15 enhances proteasomal degradation of Bid In normal lymphocytes : implications for Large granular lymphocyte leukemias. / Hodge, Deborah L.; Yang, Jun; Buschman, Matthew D.; Schaughency, Paul M.; Dang, Hong; Bere, William; Yang, Yili; Savan, Ram; Subleski, Jeff J.; Yin, Xiao-Ming; Loughran, Thomas P.; Young, Howard A.

In: Cancer Research, Vol. 69, No. 9, 01.05.2009, p. 3986-3994.

Research output: Contribution to journalArticle

Hodge, DL, Yang, J, Buschman, MD, Schaughency, PM, Dang, H, Bere, W, Yang, Y, Savan, R, Subleski, JJ, Yin, X-M, Loughran, TP & Young, HA 2009, 'Interleukin-15 enhances proteasomal degradation of Bid In normal lymphocytes: implications for Large granular lymphocyte leukemias', Cancer Research, vol. 69, no. 9, pp. 3986-3994. https://doi.org/10.1158/0008-5472.CAN-08-3735
Hodge, Deborah L. ; Yang, Jun ; Buschman, Matthew D. ; Schaughency, Paul M. ; Dang, Hong ; Bere, William ; Yang, Yili ; Savan, Ram ; Subleski, Jeff J. ; Yin, Xiao-Ming ; Loughran, Thomas P. ; Young, Howard A. / Interleukin-15 enhances proteasomal degradation of Bid In normal lymphocytes : implications for Large granular lymphocyte leukemias. In: Cancer Research. 2009 ; Vol. 69, No. 9. pp. 3986-3994.
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