The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis

Koen Dreijerink, Eleora Braga, Igor Kuzmin, Laura Geil, Fuh Mei Duh, Debora Angeloni, Berton Zbar, Michael I. Lerman, Eric J. Stanbridge, John D. Minna, Alexei Protopopov, Jingfeng Li, Vladimir Kashuba, George Klein, Eugene R. Zabarovsky

Research output: Contribution to journalArticle

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Abstract

Clear cell-type renal cell carcinomas (clear RCC) are characterized almost universally by loss of heterozygosity on chromosome 3p, which usually involves any combination of three regions: 3p25-p26 (harboring the VHL gene), 3p12-p14.2 (containing the FHIT gene), and 3p21-p22, implying inactivation of the resident tumor-suppressor genes (TSGs). For the 3p21-p22 region, the affected TSGs remain, at present, unknown. Recently, the RAS association family 1 gene (isoform RASSF1A), located at 3p21.3, has been identified as a candidate lung and breast TSG. In this report, we demonstrate aberrant silencing by hypermethylation of RASSF1A in both VHL-caused clear RCC tumors and clear RCC without VHL inactivation. We found hypermethylation of RASSF1A's GC-rich putative promoter region in most of analyzed samples, including 39 of 43 primary tumors (91%). The promoter was methylated partially or completely in all 18 RCC cell lines analyzed. Methylation of the GC-rich putative RASSF1A promoter region and loss of transcription of the corresponding mRNA were related causally. RASSF1A expression was reactivated after treatment with 5-aza-2′-deoxycytidine. Forced expression of RASSF1A transcripts in KRC/Y, a renal carcinoma cell line containing a normal and expressed VHL gene, suppressed growth on plastic dishes and anchorage-independent colony formation in soft agar. Mutant RASSF1A had reduced growth suppression activity significantly. These data suggest that RASSF1A is the candidate renal TSG gene for the 3p21.3 region.

Original languageEnglish (US)
Pages (from-to)7504-7509
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number13
DOIs
StatePublished - Jun 19 2001

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Human Chromosomes
Tumor Suppressor Genes
Carcinogenesis
Kidney
Renal Cell Carcinoma
Genes
decitabine
Genetic Promoter Regions
Cell Line
Loss of Heterozygosity
Growth
Methylation
Plastics
Agar
Neoplasms
Protein Isoforms
Chromosomes
Breast Neoplasms
Carcinoma
Lung

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. / Dreijerink, Koen; Braga, Eleora; Kuzmin, Igor; Geil, Laura; Duh, Fuh Mei; Angeloni, Debora; Zbar, Berton; Lerman, Michael I.; Stanbridge, Eric J.; Minna, John D.; Protopopov, Alexei; Li, Jingfeng; Kashuba, Vladimir; Klein, George; Zabarovsky, Eugene R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 13, 19.06.2001, p. 7504-7509.

Research output: Contribution to journalArticle

Dreijerink, K, Braga, E, Kuzmin, I, Geil, L, Duh, FM, Angeloni, D, Zbar, B, Lerman, MI, Stanbridge, EJ, Minna, JD, Protopopov, A, Li, J, Kashuba, V, Klein, G & Zabarovsky, ER 2001, 'The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 13, pp. 7504-7509. https://doi.org/10.1073/pnas.131216298
Dreijerink, Koen ; Braga, Eleora ; Kuzmin, Igor ; Geil, Laura ; Duh, Fuh Mei ; Angeloni, Debora ; Zbar, Berton ; Lerman, Michael I. ; Stanbridge, Eric J. ; Minna, John D. ; Protopopov, Alexei ; Li, Jingfeng ; Kashuba, Vladimir ; Klein, George ; Zabarovsky, Eugene R. / The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 13. pp. 7504-7509.
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abstract = "Clear cell-type renal cell carcinomas (clear RCC) are characterized almost universally by loss of heterozygosity on chromosome 3p, which usually involves any combination of three regions: 3p25-p26 (harboring the VHL gene), 3p12-p14.2 (containing the FHIT gene), and 3p21-p22, implying inactivation of the resident tumor-suppressor genes (TSGs). For the 3p21-p22 region, the affected TSGs remain, at present, unknown. Recently, the RAS association family 1 gene (isoform RASSF1A), located at 3p21.3, has been identified as a candidate lung and breast TSG. In this report, we demonstrate aberrant silencing by hypermethylation of RASSF1A in both VHL-caused clear RCC tumors and clear RCC without VHL inactivation. We found hypermethylation of RASSF1A's GC-rich putative promoter region in most of analyzed samples, including 39 of 43 primary tumors (91{\%}). The promoter was methylated partially or completely in all 18 RCC cell lines analyzed. Methylation of the GC-rich putative RASSF1A promoter region and loss of transcription of the corresponding mRNA were related causally. RASSF1A expression was reactivated after treatment with 5-aza-2′-deoxycytidine. Forced expression of RASSF1A transcripts in KRC/Y, a renal carcinoma cell line containing a normal and expressed VHL gene, suppressed growth on plastic dishes and anchorage-independent colony formation in soft agar. Mutant RASSF1A had reduced growth suppression activity significantly. These data suggest that RASSF1A is the candidate renal TSG gene for the 3p21.3 region.",
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T1 - The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis

AU - Dreijerink, Koen

AU - Braga, Eleora

AU - Kuzmin, Igor

AU - Geil, Laura

AU - Duh, Fuh Mei

AU - Angeloni, Debora

AU - Zbar, Berton

AU - Lerman, Michael I.

AU - Stanbridge, Eric J.

AU - Minna, John D.

AU - Protopopov, Alexei

AU - Li, Jingfeng

AU - Kashuba, Vladimir

AU - Klein, George

AU - Zabarovsky, Eugene R.

PY - 2001/6/19

Y1 - 2001/6/19

N2 - Clear cell-type renal cell carcinomas (clear RCC) are characterized almost universally by loss of heterozygosity on chromosome 3p, which usually involves any combination of three regions: 3p25-p26 (harboring the VHL gene), 3p12-p14.2 (containing the FHIT gene), and 3p21-p22, implying inactivation of the resident tumor-suppressor genes (TSGs). For the 3p21-p22 region, the affected TSGs remain, at present, unknown. Recently, the RAS association family 1 gene (isoform RASSF1A), located at 3p21.3, has been identified as a candidate lung and breast TSG. In this report, we demonstrate aberrant silencing by hypermethylation of RASSF1A in both VHL-caused clear RCC tumors and clear RCC without VHL inactivation. We found hypermethylation of RASSF1A's GC-rich putative promoter region in most of analyzed samples, including 39 of 43 primary tumors (91%). The promoter was methylated partially or completely in all 18 RCC cell lines analyzed. Methylation of the GC-rich putative RASSF1A promoter region and loss of transcription of the corresponding mRNA were related causally. RASSF1A expression was reactivated after treatment with 5-aza-2′-deoxycytidine. Forced expression of RASSF1A transcripts in KRC/Y, a renal carcinoma cell line containing a normal and expressed VHL gene, suppressed growth on plastic dishes and anchorage-independent colony formation in soft agar. Mutant RASSF1A had reduced growth suppression activity significantly. These data suggest that RASSF1A is the candidate renal TSG gene for the 3p21.3 region.

AB - Clear cell-type renal cell carcinomas (clear RCC) are characterized almost universally by loss of heterozygosity on chromosome 3p, which usually involves any combination of three regions: 3p25-p26 (harboring the VHL gene), 3p12-p14.2 (containing the FHIT gene), and 3p21-p22, implying inactivation of the resident tumor-suppressor genes (TSGs). For the 3p21-p22 region, the affected TSGs remain, at present, unknown. Recently, the RAS association family 1 gene (isoform RASSF1A), located at 3p21.3, has been identified as a candidate lung and breast TSG. In this report, we demonstrate aberrant silencing by hypermethylation of RASSF1A in both VHL-caused clear RCC tumors and clear RCC without VHL inactivation. We found hypermethylation of RASSF1A's GC-rich putative promoter region in most of analyzed samples, including 39 of 43 primary tumors (91%). The promoter was methylated partially or completely in all 18 RCC cell lines analyzed. Methylation of the GC-rich putative RASSF1A promoter region and loss of transcription of the corresponding mRNA were related causally. RASSF1A expression was reactivated after treatment with 5-aza-2′-deoxycytidine. Forced expression of RASSF1A transcripts in KRC/Y, a renal carcinoma cell line containing a normal and expressed VHL gene, suppressed growth on plastic dishes and anchorage-independent colony formation in soft agar. Mutant RASSF1A had reduced growth suppression activity significantly. These data suggest that RASSF1A is the candidate renal TSG gene for the 3p21.3 region.

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