title: 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.
abstract: 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.
authors.affiliation: Biological Carcinogenesis Development Program, Inc/DynCorp, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: M
authors.initials: M
authors.lastname: Beckwith
authors.forename: F W
authors.initials: FW
authors.lastname: Ruscetti
authors.forename: G K
authors.initials: GK
authors.lastname: Sing
authors.forename: W J
authors.initials: WJ
authors.lastname: Urba
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011817:Rabbits; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D007075:Immunoglobulin M; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; D018125:Receptors, Transforming Growth Factor beta; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C044203:anti-IgM; D013755:Tetradecanoylphorbol Acetate