Posttranscriptional cell cycle-dependent regulation of human FANCC expression.
The Fanconi Anemia (FA) Group C complementation group gene (FANCC) encodes a protein, FANCC, with a predicted M(r) of 63,000 daltons. FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins. Despite intensive investigation, the biologic roles of FANCC and of the other cloned FA gene products (FANCA and FANCG) remain unknown. As an approach to understanding FANCC function, we have studied the molecular regulation of FANCC expression. We found that although FANCC mRNA levels are constant throughout the cell cycle, FANCC is expressed in a cell cycle-dependent manner, with the lowest levels seen in cells synchronized at the G1/S boundary and the highest levels in the M-phase. Cell cycle-dependent regulation occurred despite deletion of the 5' and 3' FANCC untranslated regions, indicating that information in the FANCC coding sequence is sufficient to mediate cell cycle-dependent regulation. Moreover, inhibitors of proteasome function blocked the observed regulation. We conclude that FANCC expression is controlled by posttranscriptional mechanisms that are proteasome dependent. Recent work has demonstrated that the functional activity of FA proteins requires the physical interaction of at least FANCA, FANCC, and FANCG, and possibly of other FA and non-FA proteins. Our observation of dynamic control of FANCC expression by the proteasome has important implications for understanding the molecular regulation of the multiprotein complex. (Blood. 2000;95:3970-3977)
Heinrich
M C
MC
Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, OR 97207, USA. heinrich@ohsu.edu
Silvey
K V
KV
Stone
S
S
Zigler
A J
AJ
Griffith
D J
DJ
Montalto
M
M
Chai
L
L
Zhi
Y
Y
Hoatlin
M E
ME
D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000235:genetics*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000502:physiology*; D005816:Genetic Complementation Test; D006801:Humans; D009687:Nuclear Proteins; D010957:Plasmids; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins