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Identification of a Novel NOTCH-4/INT-3 RNA Species

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Identification of a Novel NOTCH-4/INT-3 RNA Species Oncogene (2000) 19, 223 ± 231 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Identi®cation of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines Akira Imatani1 and Robert Callahan*,1 1Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland, MD 20892, USA Ectopic expression of the intracellular domain of Other members of the NOTCH gene family are NOTCH-4/INT-3 leads to tumorigenesis in the mouse activated in various type of malignancies. For instance, mammary gland. This results from a gain-of-function the chromosomal translocation t(7;9)(q34;q34.3) in mutation. To evaluate gain-of-function NOTCH-4/INT- human T-cell acute lymphoblastic leukemia leads to the 3 activity in human cancers we have surveyed human expression of a truncated NOTCH-1/TAN-1 gene breast, lung, and colon carcinoma tissue culture cell lines product which is missing most of the extracellular for evidence of increased NOTCH-4/INT-3 RNA domain (Aster et al., 1994; Ellison et al., 1991). expression. High levels of a 1.8 Kb NOTCH-4/INT-3 NOTCH-1 is also activated by retroviral insertional RNA species are detected in normal human testis but not mutagenesis in certain strains of transgenic mice in a in other tissues where a 6.5 Kb species is prevalent. manner that is similar to those observed at NOTCH-4/ Transformed human cancer cell lines express the 1.8 Kb INT-3 in MMTV infected feral mice. Thus, in c-erbB2 NOTCH-4/INT-3 RNA species. We show that this RNA transgenic mice infected with MMTV some mammary species encodes a truncated form of the NOTCH-4/INT- tumors contain viral induced rearrangements of 3 intracellular domain (ICD). This novel NOTCH-4/ NOTCH-1 (Jolicoeur et al., 1998). Similarly, thymic INT-3 protein includes the CDC10 repeats and amino lymphomas in murine leukemia virus (MuLv) infected c- acid residues C-terminal to them, but is missing the myc transgenic mice contain a viral induced rearrange- CBF-1 binding region of the NOTCH-4/INT-3 ICD. ments of NOTCH-1 (Girard et al., 1996). Expression of This suggests that it has a dierent mode of action. genetically activated NOTCH-2 is also thought to Furthermore, we show that a transgene which expresses contribute to the induction of thymic lymphomas in cats the 1.8 Kb NOTCH-4/INT-3 RNA species in the (Rohn et al., 1996). In these cases the feline leukemia virus `normal' human mammary epithelial cell line MCF-10A (FeLV) has been shown to transduce the region of enables these cells to grow in soft agar. Oncogene (2000) NOTCH-2 which is analogus to the portion of 19, 223 ± 231. NOTCH-1 whose expression is activated by chromoso- mal translocation or viral induced rearrangement. In each Keywords: NOTCH-4/INT-3; activated gene product; case, whether by chromosomal translocation or viral human induced rearrangement, expression of truncated NOTCH-1 and NOTCH-2 RNA appears to represent a gain-of-function mutation. Further evidence for this conclusion is the demonstration that expression of Introduction NOTCH-1 or NOTCH-2 ICD in E1A-immortalized baby rat kidney cells confers on them the ability to grow In mammals the NOTCH gene family comprises four in soft agar and form tumors in nude mice (Capobianco et related genes that encode transmembrane receptor al., 1997). proteins which are involved in cell-fate decisions during In humans, NOTCH-4/INT-3 has been reported to development (Artavanis-Tsakonas et al., 1999). The be normally expressed in all adult tissues as a major NOTCH-4/INT-3 gene is frequently rearranged by 6.5 Kb RNA species as well as a minor 9.0 Kb splice mouse mammary tumor virus (MMTV) proviral DNA variant (Li et al., 1998). We initiated a survey of integration in mammary tumors of feral mouse strains human breast, colon, and lung carcinoma cell lines for (Gallahan et al., 1997; Robbins et al., 1992; Sarkar et al., evidence of the expression of RNA species from 1994). The transforming rearrangement of NOTCH-4/ genetically `activated' NOTCH-4/INT-3. Here we INT-3 results from the expression of the intracellular report the identi®cation and characterization of a domain of the gene product under control of the MMTV 1.8 Kb NOTCH-4/INT-3 RNA species in several promoter and represents a gain-of-function mutation. tumor cell lines that is normally only detected at high Expression of this `activated' form of NOTCH-4/INT-3 levels in the testis. in transgenic mice under the control of either the MMTV long terminal repeat (LTR) or the Whey Acidic Protein (WAP) promoter leads to a severe impairment of Results mammary gland function and to the development of mammary adenocarcinomas (Gallahan et al., 1996; NOTCH-4/INT-3 RNA expression in normal human Jhappan et al., 1992; Smith et al., 1995). tissues and tumor cell lines We and others have previously shown that NOTCH-4/ *Correspondence: R Callahan, National Cancer Institute, Building 10/Room 5B50, Bethesda, Maryland, MD 20892, USA INT-3 is expressed in several adult mouse tissues as a Received 27 July 1999; revised 30 September 1999; accepted 6.7 Kb RNA species (Gallahan and Callahan, 1997; 13 October 1999 Uyttendaele et al., 1996). In the mouse testis, NOTCH-4/ Novel NOTCH-4/INT-3 RNA species in human tumor cell lines A Imatani and R Callahan 224 INT-3 is expressed primarily as a 1.5 and 1.1 Kb RNA 1.8 Kb RNA species corresponds to sequences at the 3' species (Uyttendaele et al., 1996). Whether these RNA end of the gene (data not shown). We have used primer species correspond to splice variants or arise from a extension analysis to distinguish between the possibi- cryptic promoter within introns near the 3' end of the gene lities that the 1.8 Kb RNA species is a splice variant or has not been de®nitively determined. In a survey of is initiatated from a cryptic promoter within a normal human tissue RNA, Li et al. (1998) reported a NOTCH-4/INT-3 intron. A 37-mer oligonucleotide in major 6.7 Kb NOTCH-4/INT-3 RNA species and a exon 27, corresponding to 50417-50453 bp of the minor 9.3 Kb RNA species. The latter transcript is the complete genomic DNA sequence (Li et al., 1998), result of incomplete splicing. As shown in Figure 1, in was end-labeled with g-32P-ATP and used for primer addition to the 6.7 and 9.3 Kb NOTCH-4/INT-3 RNA extension analysis on SW480 RNA. As shown in species, we also detected a major 1.8 Kb RNA species in Figure 3, two potential transcription start sites (50314 the testis. Only low levels of this RNA species could be and 50333 bp of NOTCH-4/INT-3 genomic DNA (Li detected in the spleen, prostate, ovary, and small intestine. et al., 1998)) were detected in intron 26. We examined eight breast, seven lung and four colon carcinoma cell lines for NOTCH-4/INT-3 RNA expression (Figure 2). The 6.7 Kb RNA species was detected in seven out of eight breast carcinoma cell lines (Figure 2a), whereas only low levels of this RNA species could be found in the lung and colon carcinoma cell lines (Figure 2b). Interestingly, easily detectable levels of the 1.8 Kb NOTCH-4/INT-3 RNA species were observed in the breast carcinoma cell lines BT474 and HS578, the small cell lung carcinoma cell line H69, the non-small cell lung carcinoma cell line H157, and the colon carcinoma cell line SW480 (Figure 2). Identi®cation of the transcription start site for the 1.8 Kb NOTCH-4/INT-3 RNA species in testis and tumor cell line RNAs Using cDNA probes corresponding to dierent regions of NOTCH-4/INT-3 RNA, it was ascertained that the Figure 2 NOTCH-4/INT-3 RNA expression in normal human and human tumor tissue culture cell lines assayed by Northern blot analysis. Part A, RNA from `normal' breast epithelial cell lines: lane 1, MCF10A; lane 2, A1N4; and breast tumor cell lines: lane 3, BT474; lane 4, Hs578T; lane 5, MCF7; lane 6, MDA MD 231; lane 7, MDA MD 468; lane 8, SKBR3; lane 9, T47D; lane 10, ZR75-1; and lane 11, normal testis. Part B, RNA from small Figure 1 NOTCH-4/INT-3 RNA expression in normal human cell lung carcinoma cell lines: lane 1, NCl-H69; lane 2, NCl-H82; adult tissues. The numbers on the side indicate the size in Kb of a lane 3, NCl-H417; lane 4, NCl-H446; non-small cell lung marker species. The RNA samples were from: lane 1, spleen; lane carcinoma cell lines: lane 5, NCl-H157; lane 6, NCl-H460; lane 2, thymus; lane 3, prostate; lane 4, testis; lane 5, ovary; lane 6, 7, NCl-H358; colon carcinoma cell lines: lane 8, SW480, lane 9, small intestine; lane 7, colon; and lane 8, leukocytes. The HT29; lane 10, COLO205; lane 11, COLO320DM; and lane 12, Northern blot in the upper panel was hybridized with a 500 bp testis. The Northern blot in the upper panel of (a, b) was cDNA probe corresponding to 3' end of NOTCH-4/INT-3 (see hybridized with a 500 bp cDNA probe corresponding to 3' end of Materials and methods). In the lower panel the same blot was NOTCH-4/INT-3.
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