Abstract
TP53 (p53) is a tumor suppressor whose functions are lost or altered in most malignancies. p53 homozygous knockout (p53−/−) mice uniformly die of spontaneous malignancy, typically T-cell lymphoma. RALBP1 (RLIP76, Rlip) is a stress-protective, mercapturic acid pathway transporter protein that also functions as a Ral effector involved in clathrin-dependent endocytosis. In stark contrast to p53−/− mice, Rlip−/− mice are highly resistant to carcinogenesis. We report here that partial Rlip deficiency induced by weekly administration of an Rlip-specific phosphorothioate antisense oligonucleotide, R508, strongly inhibited spontaneous as well as benzo(a)pyrene-induced carcinogenesis in p53−/− mice. This treatment effectively prevented large-scale methylomic and transcriptomic abnormalities suggestive of inflammation found in cancer-bearing p53−/− mice. The remarkable efficiency with which Rlip deficiency suppresses spontaneous malignancy in p53−/− mice has not been observed with any previously reported pharmacologic or genetic intervention. These findings are supported by cross-breeding experiments demonstrating that hemizygous Rlip deficiency also reduces the spontaneous malignancy phenotype of p53+/− mice. Rlip is found on the cell surface, and antibodies directed against Rlip were found to inhibit growth and promote apoptosis of cell lines as effectively as Rlip siRNA. The work presented here investigates several features, including oxidative DNA damage of the Rlip-p53 association in malignant transformation, and offers a paradigm for the mechanisms of tumor suppression by p53 and the prospects of suppressing spontaneous malignancy in hereditary cancer syndromes such as Li-Fraumeni.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3918-3923 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 115 |
| Issue number | 15 |
| DOIs | |
| State | Published - Jan 1 2018 |
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Keywords
- Cancer prevention
- Cancer signalling
- Cytokine
- RALBP1
- TP53
ASJC Scopus subject areas
- General
Cite this
Rlip depletion prevents spontaneous neoplasia in TP53 null mice. / Awasthi, Sanjay; Tompkins, Joshua; Singhal, Jyotsana; Riggs, Arthur D.; Yadav, Sushma; Wu, Xiwei; Singh, Sharda; Warden, Charles; Liu, Zheng; Wang, Jinhui; Slavin, Thomas P.; Weitzel, Jeffrey N.; Yuan, Yate Ching; Awasthi, Meenakshi; Srivastava, Satish; Awasthi, Yogesh C.; Singhal, Sharad S.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 15, 01.01.2018, p. 3918-3923.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rlip depletion prevents spontaneous neoplasia in TP53 null mice
AU - Awasthi, Sanjay
AU - Tompkins, Joshua
AU - Singhal, Jyotsana
AU - Riggs, Arthur D.
AU - Yadav, Sushma
AU - Wu, Xiwei
AU - Singh, Sharda
AU - Warden, Charles
AU - Liu, Zheng
AU - Wang, Jinhui
AU - Slavin, Thomas P.
AU - Weitzel, Jeffrey N.
AU - Yuan, Yate Ching
AU - Awasthi, Meenakshi
AU - Srivastava, Satish
AU - Awasthi, Yogesh C.
AU - Singhal, Sharad S.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - TP53 (p53) is a tumor suppressor whose functions are lost or altered in most malignancies. p53 homozygous knockout (p53−/−) mice uniformly die of spontaneous malignancy, typically T-cell lymphoma. RALBP1 (RLIP76, Rlip) is a stress-protective, mercapturic acid pathway transporter protein that also functions as a Ral effector involved in clathrin-dependent endocytosis. In stark contrast to p53−/− mice, Rlip−/− mice are highly resistant to carcinogenesis. We report here that partial Rlip deficiency induced by weekly administration of an Rlip-specific phosphorothioate antisense oligonucleotide, R508, strongly inhibited spontaneous as well as benzo(a)pyrene-induced carcinogenesis in p53−/− mice. This treatment effectively prevented large-scale methylomic and transcriptomic abnormalities suggestive of inflammation found in cancer-bearing p53−/− mice. The remarkable efficiency with which Rlip deficiency suppresses spontaneous malignancy in p53−/− mice has not been observed with any previously reported pharmacologic or genetic intervention. These findings are supported by cross-breeding experiments demonstrating that hemizygous Rlip deficiency also reduces the spontaneous malignancy phenotype of p53+/− mice. Rlip is found on the cell surface, and antibodies directed against Rlip were found to inhibit growth and promote apoptosis of cell lines as effectively as Rlip siRNA. The work presented here investigates several features, including oxidative DNA damage of the Rlip-p53 association in malignant transformation, and offers a paradigm for the mechanisms of tumor suppression by p53 and the prospects of suppressing spontaneous malignancy in hereditary cancer syndromes such as Li-Fraumeni.
AB - TP53 (p53) is a tumor suppressor whose functions are lost or altered in most malignancies. p53 homozygous knockout (p53−/−) mice uniformly die of spontaneous malignancy, typically T-cell lymphoma. RALBP1 (RLIP76, Rlip) is a stress-protective, mercapturic acid pathway transporter protein that also functions as a Ral effector involved in clathrin-dependent endocytosis. In stark contrast to p53−/− mice, Rlip−/− mice are highly resistant to carcinogenesis. We report here that partial Rlip deficiency induced by weekly administration of an Rlip-specific phosphorothioate antisense oligonucleotide, R508, strongly inhibited spontaneous as well as benzo(a)pyrene-induced carcinogenesis in p53−/− mice. This treatment effectively prevented large-scale methylomic and transcriptomic abnormalities suggestive of inflammation found in cancer-bearing p53−/− mice. The remarkable efficiency with which Rlip deficiency suppresses spontaneous malignancy in p53−/− mice has not been observed with any previously reported pharmacologic or genetic intervention. These findings are supported by cross-breeding experiments demonstrating that hemizygous Rlip deficiency also reduces the spontaneous malignancy phenotype of p53+/− mice. Rlip is found on the cell surface, and antibodies directed against Rlip were found to inhibit growth and promote apoptosis of cell lines as effectively as Rlip siRNA. The work presented here investigates several features, including oxidative DNA damage of the Rlip-p53 association in malignant transformation, and offers a paradigm for the mechanisms of tumor suppression by p53 and the prospects of suppressing spontaneous malignancy in hereditary cancer syndromes such as Li-Fraumeni.
KW - Cancer prevention
KW - Cancer signalling
KW - Cytokine
KW - RALBP1
KW - TP53
UR - http://www.scopus.com/inward/record.url?scp=85045082604&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045082604&partnerID=8YFLogxK
U2 - 10.1073/pnas.1719586115
DO - 10.1073/pnas.1719586115
M3 - Article
VL - 115
SP - 3918
EP - 3923
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 15
ER -