Biomedical subjects

June X Zou

Publications and source records attributed to June X Zou.

5 recordsLinked to original sources

PubMed2006

ACTR/AIB1/SRC-3 and androgen receptor control prostate cancer cell proliferation and tumor growth through direct control of cell cycle genes.

BACKGROUND: Co-factor ACTR is frequently overexpressed and/or amplified in multiple types of tumors. The mechanism of its function in prostate cancer (CaP) is still unclear. METHODS: The effects of ACTR and androgen receptor (AR) depletion on cell proliferation and gene expression and their functions were analyzed in a panel of androgen-dependent and -independent CaP cells and CWR22 xenograft. RESULTS: ACTR and AR, but not TIF2, are required for proliferation of androgen-dependent and -independent cells, and for tumor growth. While AR depletion inhibited the expression of cyclin D1, cyclin B, and cdc2, ACTR depletion reduced the expression of cyclin E and cdk2. In response to serum stimulation, AR and ACTR are recruited to the corresponding target gene promoters to activate their expression in androgen-independent manner. CONCLUSION: These findings suggest that AR and ACTR may play important roles in androgen ablation resistance by controlling key cell cycle gene expression.

Androgens↗

PubMed2006

Direct control of cell cycle gene expression by proto-oncogene product ACTR, and its autoregulation underlies its transforming activity.

ACTR (also called AIB1 and SRC-3) was identified as a coactivator for nuclear receptors and is linked to multiple types of human cancer due to its frequent overexpression. However, the molecular mechanism of ACTR oncogenicity and its function independent of nuclear receptors remain to be defined. We demonstrate here that ACTR is required for both normal and malignant human cells to effectively enter S phase. RNA interference-mediated depletion and chromatin immunoprecipitation assays show that endogenous ACTR directly controls the expression of genes important for initiation of DNA replication, which include cdc6, cdc25A, MCM7, cyclin E, and Cdk2. Moreover, consistent with its critical role in cell cycle control, ACTR expression appears to be cell cycle regulated, which involves E2F. Interestingly, ACTR is recruited to its own promoter at the G1/S transition and activates its own expression, suggesting a positive feedback mechanism for ACTR action in the control of cell cycle progression and for its aberrant expression in cancers. Importantly, overexpression of ACTR alone transforms human mammary epithelial cells, which requires its association with E2F. These findings reveal a novel role for ACTR in cell cycle control and support the notion that the ability of aberrant ACTR to deregulate the cell cycle through E2F underlies its oncogenicity in human cancers.

Acetyltransferases↗

PubMed2004

ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance.

Overexpression or amplification of ACTR (also named AIB1, RAC3, p/CIP, TRAM-1, and SRC-3), a member of the p160 family of coactivators for nuclear hormone receptors, has been frequently detected in multiple types of human tumors, including breast cancer. However, its role in cancer cell proliferation and the underlying mechanism are unclear. Here, we show that overexpression of ACTR not only enhances estrogen-stimulated cell proliferation but also, more strikingly, completely negates the cell cycle arrest effect by tamoxifen and pure antiestrogens. Unexpectedly, we found that ACTR directly interacts, through its N-terminal domain, with E2F1 and is recruited to E2F target gene promoters. Elevation of ACTR in quiescent cells strongly stimulates the transcription of a subset of E2F-responsive genes that are associated with the G(1)/S transition. We also demonstrated, by adenovirus vector-mediated RNA interference, that ACTR is required for E2F1-mediated gene expression and the proliferation of estrogen receptor (ER)-negative breast cancer cells. Moreover, the ability of elevated ACTR to promote estrogen-independent cell proliferation depends on the function of E2F1 and the association between ACTR and E2F1, but not ER. Thus, our results reveal an essential role of ACTR in control of breast cancer cell proliferation and implicate the ACTR-E2F1 pathway as a novel mechanism in antiestrogen resistance.

Base Sequence↗

PubMed2003

Androgen-induced recruitment of RNA polymerase II to a nuclear receptor-p160 coactivator complex.

The androgen receptor, like other nuclear receptors, activates target genes by binding to hormone-responsive enhancers. Here we demonstrate that androgen induces robust recruitment of androgen receptor, members of the p160 coactivator family, and CREB-binding protein p300 specifically at the distant enhancer of prostate-specific antigen (PSA) gene. Unexpectedly, we found that RNA polymerase II (Pol II) is directly recruited to the enhancer in a hormone-dependent manner, independent of the proximal promoter, and that the isolated PSA enhancer can mediate efficient androgen induction of transcription. Inhibition of the Pol II carboxyl-terminal domain kinase activity with low concentrations of flavopiridol blocks Pol II transfer from the enhancer to the promoter and selectively abolishes PSA induction by androgen. Moreover, elevated levels of the p160 coactivator ACTR/AIB1 increase both androgen-dependent and -independent PSA expression, by facilitating Pol II recruitment to the enhancer. These results support a model in which nuclear receptors and their coactivators mediate hormone induction by serving as a staging platform for Pol II recruitment.

Adenoviridae↗

PubMed2001

Activated SRC oncogene phosphorylates R-ras and suppresses integrin activity.

One of the prominent effects of the Src kinase is to reduce cell adhesion. The small GTPase, R-Ras, affects cell adhesion by maintaining integrin activity, and the ability of R-Ras to do so can be regulated by phosphorylation of a tyrosine residue located in its effector domain by an Eph receptor kinase (Zou, J. X., Wang, B., Kalo, M. S., Zisch, A. H., Pasquale, E. B., and Ruoslahti, E. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 13813-13818). Here we show that Src regulates cell adhesion through R-Ras and integrins. Reduced substrate attachment of 293T cells transfected with the cDNA for an activated form of Src (v-Src) was accompanied by phosphorylation of endogenous R-Ras. v-Src also phosphorylated R-Ras in vitro. An activated form of Src similar to one that has been found in human cancers, Src527, shared with v-Src the ability to phosphorylate R-Ras. Stronger R-Ras phosphorylation was seen in Madin-Darby canine kidney cells cells transformed with temperature-sensitive v-Src at the permissive temperature than at the non-permissive temperature, and R-Ras and Src co-immunoprecipitated at the permissive temperature. Mutation analysis showed that the Src phosphorylation site in R-Ras was tyrosine 66, the position critical to the ability of R-Ras to support integrin activity. Finally, activated R-Ras in which tyrosine 66 is mutated to phenylalanine rendered cells partially resistant to the effects of Src on cell adhesion. Regulation of cell adhesion by Src through R-Ras may be at least partially responsible for the reduced adhesion and the resulting increased invasiveness of Src-transformed cells.

Animals↗