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Anti-IgM induces transforming growth factor-beta sensitivity in a human
B-lymphoma cell line: inhibition of growth is associated with a
downregulation of mutant p53
M Beckwith, FW Ruscetti, GK Sing, WJ Urba and DL Longo
Biological Carcinogenesis Development Program, Inc/DynCorp, National Cancer
Institute, Frederick, MD 21702, USA.
We wished to examine the role of transforming growth factor-beta (TGF-
beta) in the regulation of human lymphoma cell growth. The RL cell line is
an immunoglobulin M (IgM)+, IgD+ B lymphoma cell line, which does not
constitutively express receptors for TGF-beta, and thus has lost the
ability to respond to the inhibitory effects of TGF-beta. We demonstrate
here that anti-Ig antibodies can efficiently upregulate the expression of
TGF-beta receptors and promote sensitivity to growth inhibition by
TGF-beta. Furthermore, because TGF-beta has been shown to function in late
G1 of the cell cycle, we examined the ability of TGF- beta to modulate two
tumor suppressor proteins known to be critical regulators of the G1/S
transition, Rb and p53. Rb is a 105- to 110-kD phosphoprotein, which has
been shown to maintain its growth suppressive function when it is found in
the hypophosphorylated state. Wild-type p53 is a 53-kD phosphoprotein that
appears to be important in preventing cell-cycle progression and promoting
apoptosis in cells with DNA damage, whereas mutant p53 can overcome those
functions. We show here that TGF-beta treatment of phorbol myristate
acetate (PMA) or anti- Ig-activated RL cells results in growth inhibition
through a dual effect on Rb and mutant p53. After TGF-beta treatment, we
observe a predominance of Rb in the hypophosphorylated, growth suppressive
form. In addition, we show a decrease in levels of mRNA and protein for
mutant p53. We also show that, although these changes are sufficient to
halt progression through the cell cycle, the cells do not appear to undergo
extensive programmed cell death following 72 hours of TGF-beta treatment.
Thus, although these lymphoma cells maintain the capacity to be negatively
growth regulated by TGF-beta, the ability of TGF-beta to induce apoptosis
must be independently controlled.
Volume 85,
Issue 9,
pp. 2461-2470,
05/01/1995
Copyright © 1995 by The American Society of Hematology
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