Mutation in theDrosophila gene encoding ribosomal protein S21 causes tissue overgrowth of the hematopoietic organs

Abstract

The turnout suppressor gene overgrown hematopoietic organs-23 (oho23) of Drosophila melanogaster encodes a homologue of the human $21 ribosomal protein. Homozygous P-element insertion at chromosomal band 23B on the second chromosome ofD. melanogaster reduces drastically the expression of the $21 ribosomal protein gene and causes a massive overgrowth of the hematopoietic organs which retain, however, a compact and globular structure. Differentiation of the hemocytes is arrested and, by contrast to other mutations causing overgrowth of the hematopoeitic organs, there is no release of hemocytes in the hemolymph. Larval development is considerably delayed with growth inhibition of most larval and imaginal tissues. The $21 gene, which is represented by a single-copy gene in the genome of Drosophila, produces two transcripts of 0,3 and 0,6 kb in size. These transcripts are characterized by a difference in alternative splicing in their 3' non-coding region, cDNAs corresponding to these transcripts display an 83-amino acid open reading frame with 73,3% identity and 85,6% similarity to thehuman $21 ribosomal protein gene, These results provide a striking confirmation that ribosomal proteins are involved in the regulation of cell proliferation, as has been recently shown in the case of the Drosophila $6 ribosomal protein gene. Z 24 C A F F E I N E M O D U L A T E S A P O P T O S I S O F H U M A N L E U K E M I C C E L L S , T. Efferth, U. Fabry, P.Glatte, and R. Osieka W e investigated the modulat ion o f apoptosis , radioand chemoresis tance by caffeine (CAF), express ion o f oncoproteins, and cell cycle parameters in h a m a n ,leukemic cell l ines and mononuclear cells o f 18 patients with haematological maligancies . In K G l a cells CAF synergistically potentiated cytotoxicity and apoptosis induced by ionizing radiation (IR) or carboplatin (CPt) but attentuated induction o f apoptosis by daunorubicin (DNR). CAF also released irradiated or DNR-t rea ted K G l a cells f rom G 2 M cell cycle arrest and CPttreated cells from S phase arrest. Furthermore, CAF synergistically reduced the levels o f the apoptosis inhibitor glutathione (GSH) after irradiation or CPttreatment as compared to IR or CPt alone. In contrast , t reatment with D N R plus CAF dimished GSH levels to a lesser extent than D N R alone. W e conclude that the effects o f CAF on G S H depletion represents a m e c h a n i s m o f action by which CAF can modulate apoptosis. The modula t ing effects o f CAF on resis tance to CPt were then investigated in other permanent cell lines and leukemic cells f rom 18 patients. W h e r e a s CAF increased CPt induced cytotoxicity in the K562 celt line and its doxorubicin-resis tant subline (K562/ADM), little i f any modula t ing effect o f CAF was observed in HL-60 cells or leukemic cells from patients. Mult ivariate cluster analysis revealed an associa t ion o f CPt resistance to the express ion o f c-fos, c-N-ras, and p53. Bcl-2 expression, however, was not correlated with CPt resis tance. A weak associat ion o f CPt resis tance and low proliferative activity was found. Supported by Deutsche Krebshilfe grant W82/91D1. Mediz in ische Klinik IV der R W T H Aachen , PauwelsstraBe 30, 52057 Aachen.