Mammalian Target of Rapamycin Activator RHEB Is Frequently Overexpressed in Human Carcinomas and Is Critical and Sufficient for Skin Epithelial Carcinogenesis

Abstract

Small GTPase Ras homologue enriched in brain (RHEB) binds and activates the key metabolic regulator mTORC1, which has an important role in cancer cells, but the role of RHEB in cancer pathogenesis has not been shown. By performing a meta-analysis of published cancer cytogenetic and transcriptome databases, we defined a gain of chromosome 7q36.1-q36.3 containing the RHEB locus, an overexpression of RHEB mRNA in several different carcinoma histotypes, and an association between RHEB upregulation and poor prognosis in breast and head and neck cancers. To model gain of function in epithelial malignancy, we targeted Rheb expression to murine basal keratinocytes of transgenic mice at levels similar to those that occur in human squamous cancer cell lines. Juvenile transgenic epidermis displayed constitutive mTORC1 pathway activation, elevated cyclin D1 protein, and diffuse skin hyperplasia. Skin tumors subsequently developed with concomitant stromal angio-inflammatory foci, evidencing induction of an epidermal hypoxia-inducible factor-1 transcriptional program, and paracrine feed-forward activation of the interleukin-6-signal transducer and activator of transcription 3 pathway. Rheb-induced tumor persistence and neoplastic molecular alterations were mTORC1 dependent. Rheb markedly sensitized transgenic epidermis to squamous carcinoma induction following a single dose of Ras-activating carcinogen 7,12-dimethylbenz(a)anthracene. Our findings offer direct evidence that RHEB facilitates multistage carcinogenesis through induction of multiple oncogenic mechanisms, perhaps contributing to the poor prognosis of patients with cancers overexpressing RHEB. Cancer Res; 70(8); 3287-98. ©2010 AACR.

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

“…[134][135][136][137][138] Increased Rheb expression is associated with a poor prognosis in breast and head and neck cancers. 138 Rheb activity is dependent on farnesylation. The effects of enhanced expression of Rheb on the induction of lymphomas in the Em-Myc mouse system were examined.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…Rheb is highly expressed in some human lymphomas 31,[165][166][167] and other cancers. 168 Rheb activity is dependent on farnesylation. The effects of enhanced expression of Rheb on the induction of lymphomas in the Em-Myc mouse system were examined.…”

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

“…Activation of mTORC1 enhances protein synthesis through phosphorylation of ribosomal protein S6 kinase b-1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP), which induces cell cycle progression and growth (13). Oncogenic activation of Rheb-mTORC1 signaling has been reported to induce cancer cell survival, growth, and proliferation in multiple types of malignant tumors, and inhibition of mTORC1 is a clinical therapeutic strategy for several types of cancers (18)(19)(20)(21)(22)(23). As a specific inhibitor of mTOR, rapamycin (i.e., sirolimus or rapamune) is approved as a clinical drug for immunosuppression in transplant patients and for prevention of coronary artery stent thrombosis (24).…”