The N-terminal 178-amino-acid domain only of the SV40 large T antigen acts as a transforming suppressor of the HER-2/neu oncogene

Kao, Ming‐Ching; Liu, Guang‐Yaw; Chuang, Tzu-Chao; Lin, Yen-Shing; Wuu, Jia-An; Law, S. L.

doi:10.1038/sj.onc.1201513

Cited by 20 publications

(22 citation statements)

References 33 publications

(37 reference statements)

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“…Recently it has been reported that the J domain of T antigen is required for synergistic transactivation and binding with the transcription factor complex Tst-1-Oct6-SCIP (41). Others have shown that expression of a J domain-containing fragment of T antigen is sufficient to downregulate the Her-2 promoter, which is hyperactivated in certain breast cancers (26). Mutations in the J domain of T antigen render SV40 defective for viral DNA replication and virion assembly as well as transformation (32,42).…”

Section: Discussionmentioning

confidence: 99%

The Molecular Chaperone Activity of Simian Virus 40 Large T Antigen Is Required To Disrupt Rb-E2F Family Complexes by an ATP-Dependent Mechanism

Sullivan

Cantalupo

Pipas

2000

Molecular and Cellular Biology

107

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The simian virus 40 large T antigen (T antigen) inactivates tumor suppressor proteins and therefore has been used in numerous studies to probe the mechanisms that control cellular growth and to generate immortalized cell lines. Binding of T antigen to the Rb family of growth-regulatory proteins is necessary but not sufficient to cause transformation. The molecular mechanism underlying T-antigen inactivation of Rb function is poorly understood. In this study we show that T antigen associates with pRb and p130-E2F complexes in a stable manner. T antigen dissociates from a p130-E2F-4-DP-1 complex, coincident with the release of p130 from E2F-4-DP-1. The dissociation of this complex requires Hsc70, ATP, and a functional T-antigen J domain. We also report that the "released" E2F-DP-1 complex is competent to bind DNA containing an E2F consensus binding site. We propose that T antigen disrupts Rb-E2F family complexes through the action of its J domain and Hsc70. These findings indicate how Hsc70 supports T-antigen action and help to explain the cis requirement for a J domain and Rb binding motif in T-antigen-induced transformation. Furthermore, this is the first demonstration linking Hsc70 ATP hydrolysis to the release of E2F bound by Rb family members.The tumor suppressor proteins retinoblastoma protein (pRb) and p53 have been the focus of intense study due to their crucial role in the regulation of normal cellular growth (reviewed in references 14 and 28). T antigen can inactivate both p53 and pRb and has been used as a tool to disable these cellular signaling pathways (3,10,17,22).The Rb family is composed of at least three proteins, pRb, p107, and p130, which are critical for cell cycle regulation and are thought to have overlapping functions in different stages of the cell cycle (31). pRb, p107, and p130 proteins bind to the E2F family of transcription factors. When an Rb family member binds to E2F, E2F-mediated transactivation is inhibited, and expression of E2F-responsive genes, such as cyclins A and E and dihydrofolate reductase, is decreased (1,12,24). When phosphorylated, pRb dissociates from E2F, inducing DNA synthesis and E2F-mediated gene expression, leading to advancement of the cell cycle (9, 46).T antigen binds to the pRb proteins through an LXCXE motif (15) (see Fig. 1A for T-antigen domain map). This sequence is conserved in many pRb binding proteins, including cellular proteins such as BRG1 (13) and those expressed by other small DNA tumor viruses, such as E1A (adenovirus) and E7 (papillomavirus) (11,15,25). Mutation of the LXCXE motif renders T antigen defective for transformation (36,42,48). This suggests that T antigen's affinity for Rb family members displaces Rb from binding E2F, thus inducing transformation. However, the binding of pRb family members by T antigen is not sufficient to induce transformation (42).Another region of T antigen required for transformation is the J domain (Fig. 1A) (for a review, see reference 2). J domains are a hallmark of a class of chaperones called J proteins or D...

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Section: Discussionmentioning

confidence: 99%

The Molecular Chaperone Activity of Simian Virus 40 Large T Antigen Is Required To Disrupt Rb-E2F Family Complexes by an ATP-Dependent Mechanism

Sullivan

Cantalupo

Pipas

2000

Molecular and Cellular Biology

107

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“…13 Repression of the HER-2 function suppresses the malignant phenotypes of HER-2 overexpressing cancer cells. 14,15 The HER-2 protein is frequently overexpressed in bladder cancer. 16 -21 Our previous study and those of others indicated an association between the increased expression of the HER-2 protein and advanced tumor stage, grade and poor patient survival.…”

mentioning

confidence: 99%

No association between HER‐2 gene polymorphism at codon 655 and a risk of bladder cancer

Wang¹,

Habuchi²,

Takahashi³

et al. 2001

Intl Journal of Cancer

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Section: Discussionmentioning

confidence: 84%

“…While our studies were in progress, Kao et al (1998) reported that a deletion mutant of large T, T178, which contains only N-terminal 178 amino acids of large T, also down-regulates HER-2/neu expression and suppresses the tumorigenicity of the HER-2/neu-overexpressing ovarian carcinoma cells. These results suggest that large T and its derivative T178 may be considered as targeting agents for the treatment of HER-2/neu-overexpressing cancers Kao et al, 1998). However, a serious concern exists as large T is also a potent viral oncoprotein which can fully transform cells in culture and induce tumors in nude and transgenic mice (Tooze, 1981;Srinivasan et al, 1989;SaÈ enz Robles et al, 1994;Tevethia et al, 1997).…”

Section: Discussionmentioning

confidence: 84%

“…Taken together, these results demonstrate that the synthesis of T/t-common in the SK-T/t cell lines indeed leads to the inhibition of HER-2/neu expression. In vitro suppression of SK-OV-3 cell transformation by T/t-common Previous studies have shown that inhibition of HER-2/neu expression in the HER-2/neu-overexpressing ovarian carcinoma cell lines can lead to the suppression of transforming ability of these cells (Yu et al, 1993Zhang et al, 1995;Kao et al, 1998). To determine whether expression of T/t-common could also suppress the transformed phenotypes of HER-2/ neu-overexpressing SK-OV-3 cells, we ®rst compared the cell morphology of the SK-T/t, SK-NEO, and parental SK-OV-3 cells.…”

Section: Resultsmentioning

confidence: 99%

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The N-terminal common domain of simian virus 40 large T and small t antigens acts as a transformation suppressor of the HER-2/neu oncogene

2000

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Overexpression of HER-2/neu (also known as c-erbB-2) proto-oncogene frequently occurs in many di erent types of human cancers, including ovarian carcinoma, and is known to enhance tumor metastasis and chemoresistance. Previous studies showed that inhibition of HER-2/neu expression by various agents, such as adenovirus E1A and simian virus 40 large T, can lead to suppression of tumorigenicity of HER-2/neu-overexpressing cancer cells. Here we report that T/t-common, which contains the N-terminal common domain of simian virus 40 large T and small t antigens, could speci®cally repress the HER-2/neu promoter. When the coding sequence of T/tcommon was stably transfected into the HER-2/neuoverexpressing human ovarian carcinoma SK-OV-3 cells, the expression of HER-2/neu was dramatically reduced by the expression of T/t-common. Accordingly the tumorigenic potential of these T/t-common-expressing clones, including the ability to grow anchorage-independently and the ability to induce tumor in nu/nu mice, was also drastically suppressed. Furthermore, when T/tcommon was transiently cotransfected with the activated genomic neu into NIH3T3 cells, the transforming activity of the latter was suppressed by T/t-common in soft-agarose microcolony formation assays. Taken together, these data suggest that T/t-common may act as a transformation suppressor of the HER-2/neu oncogene.

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The N-terminal 178-amino-acid domain only of the SV40 large T antigen acts as a transforming suppressor of the HER-2/neu oncogene

Cited by 20 publications

References 33 publications

The Molecular Chaperone Activity of Simian Virus 40 Large T Antigen Is Required To Disrupt Rb-E2F Family Complexes by an ATP-Dependent Mechanism

The Molecular Chaperone Activity of Simian Virus 40 Large T Antigen Is Required To Disrupt Rb-E2F Family Complexes by an ATP-Dependent Mechanism

No association between HER‐2 gene polymorphism at codon 655 and a risk of bladder cancer

The N-terminal common domain of simian virus 40 large T and small t antigens acts as a transformation suppressor of the HER-2/neu oncogene

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