Altered expression of splicing factor, heterogeneous nuclear ribonucleoprotein A2/B1, in mouse lung neoplasia.
Our previous proteomic investigation of lung neoplasia in vitro demonstrated a high concentration of the lung cancer biomarker and splicing factor, hnRNP A2/B1, in the transformed mouse lung epithelial cell line, E9. Since changes in pre-mRNA splicing profoundly affect neoplastic progression, we examined hnRNP A2/B1 expression in chemically induced primary mouse lung tumors, an in vivo model of pulmonary adencocarcinoma. Tumor hnRNP A2/B1 content and spatial distribution assessed by immunohistochemistry varied with stage of progression, genetic background, and whether tumors were induced by a single agent (urethane) or by 2-stage initiation/promotion (3-methylcholanthrene/butylated hydroxytoluene) carcinogenesis. To address mechanisms governing hnRNP A2/B1 expression changes, we utilized in vitro models. hnRNP A2/B1 protein was overexpressed in E9, the spontaneous tranformant of immortalized but non-neoplastic E10 cells, but expression was not strictly a function of enhanced proliferative rate in neoplastic cells. Elevated mRNA content was positively associated with cell division in both E10 and E9, but hnRNP A2/B1 protein levels decreased in proliferating E10 cells. The increased mRNA reflected enhanced mRNA stability, as shown by measuring time-dependent mRNA decay after inhibiting transcription. Dysregulation of hnRNP A2/B1 expression during lung neoplasia in vivo thus depends on complex gene-environmental interactions that affect cell type-specific changes in mRNA processing and, most probably, the rates of translation and/or protein degradation.
Peebles
Katherine A
KA
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado 80215, USA.
Dwyer-Nield
Lori D
LD
Malkinson
Alvin M
AM
D000818:Animals; D014408:Biomarkers, Tumor; D002084:Butylated Hydroxytoluene; D002273:Carcinogens; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D006207:Half-Life; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics*; D008168:Lung / Q000166:cytology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity; D015854:Up-Regulation; D014520:Urethane
D014408:Biomarkers, Tumor; D002273:Carcinogens; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D012333:RNA, Messenger; C439768:hnRNP A2; D002084:Butylated Hydroxytoluene; D014520:Urethane; D008748:Methylcholanthrene