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PMID: 14634209 Published · ppublish English Journal Article

Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 25 ·2003-12-09 ·Pages 14982-7

Bliskovsky V, Ramsay ES, Scott J, DuBois W, Shi W, Zhang S, Qian X, Lowy DR, Mock BA

Abstract

Susceptibility to mouse plasmacytomagenesis is a complex genetic trait controlled by several Pctr loci (Pctr1, Pctr2, etc). Congenic strain analysis narrowed the genetic interval surrounding the Pctr2 locus, and genes identified in the interval were sequenced from susceptible BALB/c and resistant DBA/2 mice. Frap (FKBP12 rapamycin-associated protein, mTOR, RAFT) was the only gene differing in amino acid sequence between alleles that correlated with strain sensitivity to tumor development. The in vitro kinase activity of the BALB/c FRAP allele was lower than the DBA/2 allele; phosphorylation of p53 and PHAS1/4EBP1 (properties of heat and acid stability/eukaryotic initiation factor 4E-binding protein) and autophosphorylation of FRAP were less efficient with the BALB/c allele. FRAP also suppressed transformation of NIH 3T3 cells by ras, with DBA/2 FRAP being more efficient than BALB/c FRAP. Rapamycin, a specific inhibitor of FRAP, did not inhibit growth of plasmacytoma cell lines. These studies identify Frap as a candidate tumor suppressor gene, in contrast to many reports that have focused on its prooncogenic properties. Frap may be similar to Tgfb and E2f in exerting both positive and negative growth-regulatory signals, depending on the timing, pathway, or tumor system involved. The failure of rapamycin to inhibit plasma cell tumor growth suggests that FRAP antagonists may not be appropriate for the treatment of plasma cell tumors. Pctr2 joins Pctr1 in possessing alleles that modify susceptibility to plasmacytomagenesis by encoding differences in efficiency of function (efficiency alleles), rather than all-or-none, gain-of-function, or loss-of-function alleles. By analogy, human cancer may also result from the combined effects of several inefficient alleles.

MeSH Terms
Alleles Amino Acid Sequence Animals Blotting, Western Carrier Proteins Cell Division Cell Line, Tumor Cell Transformation, Neoplastic DNA/chemistry Genes, Tumor Suppressor Genotype Humans Mice Mice, Inbred BALB C Mice, Inbred DBA Models, Genetic Molecular Sequence Data NIH 3T3 Cells Phenotype Phosphorylation Phosphotransferases (Alcohol Group Acceptor)/genetics Plasmacytoma/genetics,metabolism Plasmids/metabolism Polymerase Chain Reaction Sequence Homology, Amino Acid Sirolimus/pharmacology TOR Serine-Threonine Kinases Time Factors
Chemicals
Carrier Proteins DNA Phosphotransferases (Alcohol Group Acceptor) MTOR protein, human mTOR protein, mouse TOR Serine-Threonine Kinases Sirolimus
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Bliskovsky Valery
Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA.
Ramsay Edward S
Scott John
DuBois Wendy
Shi Wei
Zhang Shuling
Qian Xiaolan
Lowy Douglas R
Mock Beverly A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.2431627100
Published
2003-12-09
Epub
2003-00-21
Pages
14982-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC299869
Subset
IM
Databases
GENBANK
AF091392, AF091505, AF091506, AF092074, AF092075, AF092076, AF092077, AF092078, AF092079, AF092080, AF092081, AF092082, AF092083, AF092084, AF097512, AF107563, AF107564, AF152839, AF152840, AF152841, AH008266, AH008346, B07891, B07892, B07893, B07894, B07895, B07896, B07897, B07898, B07899, B07900, B07901, B07902, B07903, B07904, B07905, B07906, B07907, B07908, B07909, B07910, B07911, B07912, B07913, B07914, B07915, B07916, B07917, B07918, B07919, B07920, B07921, B07922, B07923, B07924, B07925, B07926, B07927, B07928, B07929, B07930, B07931, B07932, B07933, B07934, B07935, B07936, B07937, B07938, B07939, B07940, B07941, B07942, B07943, B07944, B07945, B07946, B07947, B07948, B18208, B18209, B18210, B18211, B18212, B18213, B18214, B18215, B18216, B18217, B18218, B18219, B18220, B18221, B18222, B18223, B18224
RefSeq
NM_016699, NM_019393, NM_019781
External Links
PubMed source DOI: 10.1073/pnas.2431627100 PMC Full Text View journal details
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