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Expression of N-terminally truncated isoforms of CDP/CUX is increased in human uterine leiomyomas
Nam Sung Moon1, Wendy Rong Zeng, Peter Premdas
1Molecular Oncology Group, McGill University Health Center, Montreal, Quebec, Canada.
Abstract:
Genetic analyses and mRNA expression studies have implicated CUTL1 as a candidate tumor-suppressor gene in uterine leiomyomas and breast cancers. However, modulation of CDP/Cux, the protein encoded by CUTL1, does not agree with this notion. The activity of CDP/Cux, which is the DNA binding subunit of HiNF-D, was upregulated as normal cells progressed into S phase and constitutively elevated in several tumor cell lines. Activation of CDP/Cux at the G(1)/S transition involved the proteolytic processing of the protein to generate a shorter isoform. Uterine leiomyomas represent a unique reagent for molecular analysis because they are resected as homogeneous tumor tissue together with the adjacent normal myometrium and they are often very large. In the present study, proteins were isolated from 16 pairs of matched tumors and adjacent myometrium and analyzed by Western blot and electrophoretic mobility shift assays. Strikingly, in 11/16 tumors, the steady-state level of small CDP/Cux isoforms was increased compared to normal control tissue. Where tested, a corresponding increase in CDP/Cux stable DNA binding activity was observed. DNA sequencing analysis of CUTL1 cDNAs from 6 leiomyomas, including 4 with LOH of CUTL1, did not reveal any gross rearrangement or point mutations. Altogether these findings suggest that CUTL1 is probably not the tumor suppressor on 7q22. Moreover, the frequent increase in smaller CDP/Cux isoforms indicates that molecular events associated with the truncation of CDP/Cux proteins may be selected in uterine leiomyomas.
Insights
CUTL1 is likely not a tumor suppressor gene in uterine leiomyomas. Instead, increased levels of smaller CDP/Cux protein isoforms suggest their truncation may be selected in these tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Previous studies suggested CUTL1 as a tumor suppressor in uterine leiomyomas and breast cancers.
- However, the protein product of CUTL1, CDP/Cux, shows increased activity in tumor cells and during cell cycle progression.
- CDP/Cux is the DNA binding subunit of HiNF-D and its activation at G1/S transition involves proteolytic processing.
Purpose of the Study:
- To investigate the role of CUTL1 and its protein product CDP/Cux in uterine leiomyomas.
- To determine if CUTL1 acts as a tumor suppressor or if alterations in CDP/Cux protein isoforms are associated with leiomyoma development.
Main Methods:
- Western blot analysis of proteins from matched uterine leiomyoma and myometrium samples.
- Electrophoretic mobility shift assays to assess DNA binding activity of CDP/Cux.
- DNA sequencing of CUTL1 cDNAs from leiomyomas, including those with loss of heterozygosity (LOH).
Main Results:
- Increased steady-state levels of smaller CDP/Cux isoforms were observed in 11 out of 16 uterine leiomyoma tumors compared to normal myometrium.
- A corresponding increase in CDP/Cux DNA binding activity was detected in tumors with elevated smaller isoforms.
- No gross rearrangements or point mutations in CUTL1 were found in the analyzed leiomyoma cDNAs.
Conclusions:
- The findings suggest that CUTL1 is unlikely to be the tumor suppressor gene located on chromosome 7q22.
- The frequent increase in truncated CDP/Cux isoforms indicates that molecular events leading to protein truncation may be selected during uterine leiomyoma development.
- These results challenge the tumor-suppressor hypothesis for CUTL1 in uterine leiomyomas.
