K-ras 4A and 4B are co-expressed widely in human tissues, and their ratio is altered in sporadic colorectal cancer.
Ras activating mutations result in constitutive activation of Ras signalling pathways and occur in 30% of human malignancies. K-ras encodes two splice variants, K-ras 4A and 4B, and K-ras activating mutations which jointly affect both isoforms are prevalent in lung, pancreatic and colorectal cancers. Using RT-PCR we examined their expression in normal adult human tissues and addressed whether K-ras splicing is altered in sporadic colorectal cancer by comparing normal colon with colon carcinoma cell lines, and 'matched' tumour and tumour-free colon tissues from the same patient. K-ras 4B was expressed ubiquitously and was the predominant splice variant. K-ras 4A was expressed differentially, with detection in colorectal tumours and cell lines, and normal colon, pancreas and lung--sites where tumours with K-ras activating mutations arise. Both K-ras splice variants were co-expressed by single colon carcinoma cells. The K-ras 4A/4B ratio was significantly reduced in all 6 cell lines examined, including two that lacked K-ras activating mutations, and in 4/9 primary adenocarcinomas. We conclude that K-ras activating mutations do not affect K-ras splicing per se, both isoforms may play a role in neoplastic progression, and altered splicing of either the K-ras proto-oncogene or oncogene, in favour of K-ras 4B, may modulate tumour development.
Plowman
S J
SJ
Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
Berry
R L
RL
Bader
S A
SA
Luo
F
F
Arends
M J
MJ
Harrison
D J
DJ
Hooper
M L
ML
Patek
C E
CE
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger