RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies

Vladimir I. Kashuba, Jingfeng Li, Fuli Wang, Vera N. Senchenko, Alexey Protopopov, Alena Malyukova, Alexey S. Kutsenko, Elena Kadyrova, Veronika I. Zabarovska, Olga V. Muravenko, Alexander V. Zelenin, Lev L. Kisselev, Igor Kuzmin, John D. Minna, Gösta Winberg, Ingemar Ernberg, Eleonora Braga, Michael I. Lerman, George Klein, Eugene R. Zabarovsky

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Abstract

Chromosome 3p21.3 region is frequently (>90%) deleted in lung and other major human carcinomas. We subdivided 3p21.3 into LUCA and AP20 subregions and discovered frequent homozygous deletions (10-18%) in both subregions. This finding strongly implies that they harbor multiple tumor suppressor genes involved in the origin and/or development of major epithelial cancers. In this study, we performed an initial analysis of RBSP3/HYA22, a candidate tumor suppressor genes located in the AP20 region. Two sequence splice variants of RBSP3/HYA22 (A and B) were identified, and we provide evidence for their tumor suppressor function. By sequence analysis RBSP3/HYA22 belongs to a gene family of small C-terminal domain phosphatases that may control the RNA polymerase II transcription machinery. Expression of the gene was drastically (>20-fold) decreased in 11 of 12 analyzed carcinoma cell lines and in three of eight tumor biopsies. We report missense and nonsense mutations in tumors where RBSP3/HYA22 was expressed, growth suppression with regulated transgenes in culture, suppression of tumor formation in severe combined immunodeficient mice, and dephosphorylation of ppRB by RBSP3/HYA22, presumably leading to a block of the cell cycle at the G1/S boundary.

Original languageEnglish (US)
Pages (from-to)4906-4911
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number14
DOIs
StatePublished - Apr 6 2004

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Tumor Suppressor Genes
Neoplasms
Carcinoma
SCID Mice
RNA Polymerase II
Nonsense Codon
Missense Mutation
Transgenes
Phosphoric Monoester Hydrolases
Sequence Analysis
Cell Cycle
Chromosomes
Biopsy
Gene Expression
Cell Line
Lung
Growth
Genes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Kashuba, V. I., Li, J., Wang, F., Senchenko, V. N., Protopopov, A., Malyukova, A., ... Zabarovsky, E. R. (2004). RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies. Proceedings of the National Academy of Sciences of the United States of America, 101(14), 4906-4911. https://doi.org/10.1073/pnas.0401238101

RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies. / Kashuba, Vladimir I.; Li, Jingfeng; Wang, Fuli; Senchenko, Vera N.; Protopopov, Alexey; Malyukova, Alena; Kutsenko, Alexey S.; Kadyrova, Elena; Zabarovska, Veronika I.; Muravenko, Olga V.; Zelenin, Alexander V.; Kisselev, Lev L.; Kuzmin, Igor; Minna, John D.; Winberg, Gösta; Ernberg, Ingemar; Braga, Eleonora; Lerman, Michael I.; Klein, George; Zabarovsky, Eugene R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 14, 06.04.2004, p. 4906-4911.

Research output: Contribution to journalArticle

Kashuba, VI, Li, J, Wang, F, Senchenko, VN, Protopopov, A, Malyukova, A, Kutsenko, AS, Kadyrova, E, Zabarovska, VI, Muravenko, OV, Zelenin, AV, Kisselev, LL, Kuzmin, I, Minna, JD, Winberg, G, Ernberg, I, Braga, E, Lerman, MI, Klein, G & Zabarovsky, ER 2004, 'RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies', Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 14, pp. 4906-4911. https://doi.org/10.1073/pnas.0401238101
Kashuba, Vladimir I. ; Li, Jingfeng ; Wang, Fuli ; Senchenko, Vera N. ; Protopopov, Alexey ; Malyukova, Alena ; Kutsenko, Alexey S. ; Kadyrova, Elena ; Zabarovska, Veronika I. ; Muravenko, Olga V. ; Zelenin, Alexander V. ; Kisselev, Lev L. ; Kuzmin, Igor ; Minna, John D. ; Winberg, Gösta ; Ernberg, Ingemar ; Braga, Eleonora ; Lerman, Michael I. ; Klein, George ; Zabarovsky, Eugene R. / RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 14. pp. 4906-4911.
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AU - Li, Jingfeng

AU - Wang, Fuli

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AU - Protopopov, Alexey

AU - Malyukova, Alena

AU - Kutsenko, Alexey S.

AU - Kadyrova, Elena

AU - Zabarovska, Veronika I.

AU - Muravenko, Olga V.

AU - Zelenin, Alexander V.

AU - Kisselev, Lev L.

AU - Kuzmin, Igor

AU - Minna, John D.

AU - Winberg, Gösta

AU - Ernberg, Ingemar

AU - Braga, Eleonora

AU - Lerman, Michael I.

AU - Klein, George

AU - Zabarovsky, Eugene R.

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N2 - Chromosome 3p21.3 region is frequently (>90%) deleted in lung and other major human carcinomas. We subdivided 3p21.3 into LUCA and AP20 subregions and discovered frequent homozygous deletions (10-18%) in both subregions. This finding strongly implies that they harbor multiple tumor suppressor genes involved in the origin and/or development of major epithelial cancers. In this study, we performed an initial analysis of RBSP3/HYA22, a candidate tumor suppressor genes located in the AP20 region. Two sequence splice variants of RBSP3/HYA22 (A and B) were identified, and we provide evidence for their tumor suppressor function. By sequence analysis RBSP3/HYA22 belongs to a gene family of small C-terminal domain phosphatases that may control the RNA polymerase II transcription machinery. Expression of the gene was drastically (>20-fold) decreased in 11 of 12 analyzed carcinoma cell lines and in three of eight tumor biopsies. We report missense and nonsense mutations in tumors where RBSP3/HYA22 was expressed, growth suppression with regulated transgenes in culture, suppression of tumor formation in severe combined immunodeficient mice, and dephosphorylation of ppRB by RBSP3/HYA22, presumably leading to a block of the cell cycle at the G1/S boundary.

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