Tumor promoter induces high mobility group HMG-Y protein expression in transformation-sensitive but not -resistant cells.
Elevated levels of high mobility group (HMG) nonhistone chromosomal proteins I and Y, alternatively spliced members of the HMG-I(Y) family of architectural transcription factors, have been linked with human cancer and with neo-plastic and metastatic phenotypes in model systems. To investigate whether HMG-I(Y) proteins may influence susceptibility to neoplastic transformation, HMG-I(Y) mRNA and protein levels were compared in the JB6 murine model of neoplastic progression. HMG-I(Y) mRNAs were expressed at very low levels in preneoplastic, transformation-resistant (P-) cell lines and were constitutively expressed at much higher levels in both transformation-sensitive (P +) and transformed (Tx) tumorigenic cell lines. HMG-I(Y) mRNAs were induced to higher levels by the tumor promoter 12-O-tetradecanoylphorbol acetate (TPA) and were sustained longer in P+ than in P- cells. Nevertheless, in both P- and P+ cells, primer extension analysis revealed that the same four major HMG-I(Y) gene transcription start sites were utilized with or without TPA treatment. RT-PCR revealed that there was always slightly more Y than I form mRNA present in all of the variant JB6 cell lines. Immunoblotting indicated that both HMG-I and -Y proteins increased in P + cells in response to TPA treatment. Remarkably, in P- cells treated with TPA, only HMG-I (and not HMG-Y) protein levels increased. This unique differential TPA-induction of the HMG-Y protein in JB6 variants suggests a role for HMG-Y in mediating tumor promoter-induced neoplastic transformation. Furthermore, these results demonstrate that HMG-I and Y protein translation and/or stability is differently regulated in JB6 P- cells and provide the first indication that I and Y proteins may have different functions.
Laboratory of Biochemical Physiology, Frederick Cancer Research and Development Center, National Cancer Institute, Maryland 21702, USA.
J L
JL
Cmarik
Y
Y
Li
S A
SA
Ogram
H
H
Min
R
R
Reeves
N H
NH
Colburn
D017398:Alternative Splicing; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D025741:HMGA1a Protein; D006609:High Mobility Group Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D012878:Skin Neoplasms / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic
D002273:Carcinogens; D006609:High Mobility Group Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors; D025741:HMGA1a Protein; D013755:Tetradecanoylphorbol Acetate