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Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers.
Methods Enzymol. 2006; 407:455-68.ME

Abstract

ARHI is a maternally imprinted tumor suppressor gene that is downregulated in 60% of ovarian and breast cancers. Loss of ARHI expression is associated with tumor progression in breast cancer and decreased disease-free survival in ovarian cancer. ARHI encodes a 26-kDa protein with 55-62% homology to Ras and Rap. In contrast to Ras, ARHI inhibits growth, motility, and invasion. ARHI contains a unique 34 amino-acid extension at its N-terminus and differs from Ras in residues critical for GTPase activity and for its putative effector function. Deletion of ARHI's unique N-terminal extension markedly reduces its inhibitory effect on cell growth. The gene maps to chromosome 1p31 at a site of LOH in 40% of ovarian and breast cancers. Mutations have not been detected, but the remaining allele is silenced by methylation in approximately 10-15 % of cases. In the remaining cancers, ARHI is downregulated by transcriptional mechanisms that involve E2F1 and E2F4, as well as by the loss of RNA binding proteins that decrease the half-life of ARHI mRNA. Transgenic expression of human ARHI in mice produces small stature, induces ovarian atrophy, and prevents postpartum milk production. Reexpression of ARHI in cancer cells inhibits signaling through Ras/Map and PI3 kinase, upregulates P21(WAF1/CIP1), downregulates cyclin D1, induces JNK, and inhibits signaling through STAT3. Marked overexpression of ARHI with a dual adenoviral vector induces caspase-independent, calpain-dependent apoptosis. When ARHI is expressed from a doxycycline-inducible promoter at more physiological levels, autophagy is induced, rather than apoptosis. Growth of ovarian and breast cancer xenografts is reversibly suppressed by ARHI, but expression of the NTD mutant produced only a limited inhibitory effect on growth of xenografts.

Authors+Show Affiliations

The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16757345

Citation

Yu, Yinhua, et al. "Biochemistry and Biology of ARHI (DIRAS3), an Imprinted Tumor Suppressor Gene Whose Expression Is Lost in Ovarian and Breast Cancers." Methods in Enzymology, vol. 407, 2006, pp. 455-68.
Yu Y, Luo R, Lu Z, et al. Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. Methods Enzymol. 2006;407:455-68.
Yu, Y., Luo, R., Lu, Z., Wei Feng, W., Badgwell, D., Issa, J. P., Rosen, D. G., Liu, J., & Bast, R. C. (2006). Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. Methods in Enzymology, 407, 455-68.
Yu Y, et al. Biochemistry and Biology of ARHI (DIRAS3), an Imprinted Tumor Suppressor Gene Whose Expression Is Lost in Ovarian and Breast Cancers. Methods Enzymol. 2006;407:455-68. PubMed PMID: 16757345.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. AU - Yu,Yinhua, AU - Luo,Robert, AU - Lu,Zhen, AU - Wei Feng,Wei, AU - Badgwell,Donna, AU - Issa,Jean-Pierre, AU - Rosen,Daniel G, AU - Liu,Jinsong, AU - Bast,Robert C,Jr PY - 2006/6/8/pubmed PY - 2008/6/20/medline PY - 2006/6/8/entrez SP - 455 EP - 68 JF - Methods in enzymology JO - Methods Enzymol VL - 407 N2 - ARHI is a maternally imprinted tumor suppressor gene that is downregulated in 60% of ovarian and breast cancers. Loss of ARHI expression is associated with tumor progression in breast cancer and decreased disease-free survival in ovarian cancer. ARHI encodes a 26-kDa protein with 55-62% homology to Ras and Rap. In contrast to Ras, ARHI inhibits growth, motility, and invasion. ARHI contains a unique 34 amino-acid extension at its N-terminus and differs from Ras in residues critical for GTPase activity and for its putative effector function. Deletion of ARHI's unique N-terminal extension markedly reduces its inhibitory effect on cell growth. The gene maps to chromosome 1p31 at a site of LOH in 40% of ovarian and breast cancers. Mutations have not been detected, but the remaining allele is silenced by methylation in approximately 10-15 % of cases. In the remaining cancers, ARHI is downregulated by transcriptional mechanisms that involve E2F1 and E2F4, as well as by the loss of RNA binding proteins that decrease the half-life of ARHI mRNA. Transgenic expression of human ARHI in mice produces small stature, induces ovarian atrophy, and prevents postpartum milk production. Reexpression of ARHI in cancer cells inhibits signaling through Ras/Map and PI3 kinase, upregulates P21(WAF1/CIP1), downregulates cyclin D1, induces JNK, and inhibits signaling through STAT3. Marked overexpression of ARHI with a dual adenoviral vector induces caspase-independent, calpain-dependent apoptosis. When ARHI is expressed from a doxycycline-inducible promoter at more physiological levels, autophagy is induced, rather than apoptosis. Growth of ovarian and breast cancer xenografts is reversibly suppressed by ARHI, but expression of the NTD mutant produced only a limited inhibitory effect on growth of xenografts. SN - 0076-6879 UR - https://www.unboundmedicine.com/medline/citation/16757345/Biochemistry_and_biology_of_ARHI__DIRAS3__an_imprinted_tumor_suppressor_gene_whose_expression_is_lost_in_ovarian_and_breast_cancers_ DB - PRIME DP - Unbound Medicine ER -