Functional uncoupling of the Janus kinase 3-Stat5 pathway in malignant growth of human T cell leukemia virus type 1-transformed human T cells. J Immunol 2000 Nov 01;165(9):5097-104
Date
10/25/2000Pubmed ID
11046040DOI
10.4049/jimmunol.165.9.5097Scopus ID
2-s2.0-0034327770 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
Human T cell leukemia virus type 1 (HTLV-1) transforms cytokine-dependent T lymphocytes and causes adult T cell leukemia. Janus tyrosine kinase (Jak)3 and transcription factors Stat5a and Stat5b are essential for the proliferation of normal T cells and are constitutively hyperactivated in both HTLV-1-transformed human T cell lines and lymphocytes isolated from HTLV-1-infected patients; therefore, a critical role for the Jak3-Stat5 pathway in the progression of this disease has been postulated. We recently reported that tyrphostin AG-490 selectively blocked IL-2 activation of Jak3/Stat5 and growth of murine T cell lines. Here we demonstrate that disruption of Jak3/Stat5a/b signaling with AG-490 (50 microM) blocked the proliferation of primary human T lymphocytes, but paradoxically failed to inhibit the proliferation of HTLV-1-transformed human T cell lines, HuT-102 and MT-2. Structural homologues of AG-490 also inhibited the proliferation of primary human T cells, but not HTLV-1-infected cells. Disruption of constitutive Jak3/Stat5 activation by AG-490 was demonstrated by inhibition of 1) tyrosine phosphorylation of Jak3, Stat5a (Tyr(694)), and Stat5b (Tyr(699)); 2) serine phosphorylation of Stat5a (Ser(726)) as determined by a novel phosphospecific Ab; and 3) Stat5a/b DNA binding to the Stat5-responsive beta-casein promoter. In contrast, AG-490 had no effect on DNA binding by p50/p65 components of NF-kappaB, a transcription factor activated by the HTLV-1-encoded phosphoprotein, Tax. Collectively, these data suggest that the Jak3-Stat5 pathway in HTLV-1-transformed T cells has become functionally redundant for proliferation. Reversal of this functional uncoupling may be required before Jak3/Stat5 inhibitors will be useful in the treatment of this malignancy.
Author List
Kirken RA, Erwin RA, Wang L, Wang Y, Rui H, Farrar WLMESH terms used to index this publication - Major topics in bold
Cell Line, TransformedCell Transformation, Neoplastic
Cell Transformation, Viral
DNA-Binding Proteins
Enzyme Inhibitors
Growth Inhibitors
Human T-lymphotropic virus 1
Humans
Immunosuppressive Agents
Interleukin-15
Interleukin-2
Janus Kinase 3
Lymphocyte Activation
Milk Proteins
NF-kappa B
Nuclear Proteins
Phosphorylation
Phytohemagglutinins
Protein-Tyrosine Kinases
STAT5 Transcription Factor
Serine
Signal Transduction
T-Lymphocytes
Trans-Activators
Tumor Cells, Cultured
Tumor Suppressor Proteins
Tyrosine
Tyrphostins
