193 research outputs found
CD20 and CD40 mediated mitogenic responses in B-lineage acute lymphoblastic leukaemia
Activation of CD20, a cross-membrane ion channel, induces cell cycle progression from G0 to G1 in B lymphocytes. Subsequent activation of CD40, a membrane receptor of the nerve growth factor receptor superfamily, transits the B cells to the S phase. CD40 may also act synergistically in combination with IL-4 (B lymphocytes) or IL-3/IL-7 (B-cell precursors). We investigated the proliferative responses of B-lineage acute lymphoblastic leukaemia (ALL) cells to CD20/CD40 activation. In 18/56 ALL cases, CD20 activation resulted in significant increases in DNA synthesis. Similar, although more moderate, effects were seen of activation of CD40 in 10/44 cases. Responses to CD20 or CD40 activation were independent of co-stimulation with IL-3, IL-4 or IL-7, and various cocktails of the different growth stimuli did not act synergistically
Distinct cytoplasmic regions of the human granulocyte colony-stimulating factor receptor involved in induction of proliferation and maturation
The granulocyte colony-stimulating factor receptor (G-CSF-R) transduces
signals important for the proliferation and maturation of myeloid
progenitor cells. To identify functionally important regions in the
cytoplasmic domain of the G-CSF-R, we compared the actions of the
wild-type receptor, two mutants, and a natural splice variant in
transfectants of the mouse pro-B cell line BAF3 and two myeloid cell
lines, 32D and L-GM. A region of 55 amino acids adjacent to the
transmembrane domain was found to be sufficient for generating a growth
signal. The immediate downstream sequence of 30 amino acids substantially
enhanced the growth signaling in the three cell lines. In contrast, the
carboxy-terminal part of 98 amino acids strongly inhibited growth
signaling in the two myeloid cell lines but not in BAF3 cells. Truncation
of this region lead to an inability of the G-CSF-R to transduce maturation
signals in L-GM cells. An alternative carboxy tail present in a splice
variant of the G-CSF-R also inhibited growth signaling, notably in both
the myeloid cells and BAF3 cells, but appeared not to be involved in
maturation
G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact
Truncated granulocyte colony-stimulating factor receptors (G-CSF-Rs) are
implicated in severe congenital neutropenia (SCN) and the consecutive
development of acute myeloid leukemia (AML). Mice expressing G-CSF-R
truncation mutants (gcsfr-d715) show defective receptor internalization,
an increased signal transducer and activator of transcription 5
(STAT5)/STAT3 activation ratio, and hyperproliferative responses to G-CSF
treatment. We determined whether a lack of negative feedback by suppressor
of cytokine signaling (SOCS) proteins contributes to the signaling
abnormalities of G-CSF-R-d715. Expression of SOCS3 transcripts in bone
marrow cells from G-CSF-treated gcsfr-d715 mice was approximately 60%
lower than in wild-type (WT) littermates. SOCS3 efficiently suppressed
STAT3 and STAT5 activation by WT G-CSF-R in luciferase reporter assays. In
contrast, while SOCS3 still inhibited STAT3 activation by G-CSF-R-d715,
STAT5 activation was no longer affected. This was due mainly to loss of
the SOCS3 recruitment site Tyr729, with an additional contribution of the
internalization defects of G-CSF-R-d715. Because Tyr729 is also a docking
site for the Src homology 2-containing protein tyrosine phosphatase-2
(SHP-2), which binds to and inactivates STAT5, we suggest a model in which
reduced SOCS3 expression, combined with the loss of recruitment of both
SOCS3 and SHP-2 to the activated receptor complex, determine the increased
STAT5/STAT3 activation ratio and the resulting signaling abnormalities
projected by truncated G-CSF-R mutants
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