Reciprocal Induction of MDM2 and MYCN in Neural and Neuroendocrine Cancers.

MYC family oncoproteins MYC, MYCN, and MYCL are deregulated in diverse cancers and via diverse mechanisms. Recent studies established a novel form of MYCN regulation in MYCN-overexpressing retinoblastoma and neuroblastoma cells in which the MDM2 oncoprotein promotes MYCN translation and MYCN-dependent proliferation via a p53-independent mechanism. However, it is unclear if MDM2 also promotes expression of other MYC family members and has similar effects in other cancers.

A novel thyroid hormone receptor isoform, TRβ2-46, promotes SKP2 expression and retinoblastoma cell proliferation.

Retinoblastoma is a childhood retinal tumor that develops from cone photoreceptor precursors in response to inactivating mutations and loss of functional RB protein. The cone precursor's response to RB loss involves cell type-specific signaling circuitry that helps to drive tumorigenesis. One component of the cone precursor circuitry, the thyroid hormone receptor β2 (TRβ2), enables the aberrant proliferation of diverse RB-deficient cells in part by opposing the down-regulation of S-phase kinase-associated protein 2 (SKP2) by the more widely expressed and tumor-suppressive TRβ1.

SKP2 Activation by Thyroid Hormone Receptor β2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells.

Germline mutations strongly predispose humans to cone precursor-derived retinoblastomas and strongly predispose mice to pituitary tumors, yet shared cell type-specific circuitry that sensitizes these different cell types to the loss of has not been defined. Here we show that the cell type-restricted thyroid hormone receptor isoform TRβ2 sensitizes to loss in both settings by antagonizing the widely expressed and tumor-suppressive TRβ1. TRβ2 promoted expression of the E3 ubiquitin ligase SKP2, a critical factor for -mutant tumors, by enabling EMI1/FBXO5-dependent inhibition of SKP2 degradation.

Rb suppresses human cone-precursor-derived retinoblastoma tumours.

Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear.

Identification of PITX1 as a TERT suppressor gene located on human chromosome 5.

Telomerase, a ribonucleoprotein enzyme that maintains telomere length, is crucial for cellular immortalization and cancer progression. Telomerase activity is attributed primarily to the expression of telomerase reverse transcriptase (TERT). Using microcell-mediated chromosome transfer (MMCT) into the mouse melanoma cell line B16F10, we previously found that human chromosome 5 carries a gene, or genes, that can negatively regulate TERT expression (H.

Localization of an hTERT repressor region on human chromosome 3p21.3 using chromosome engineering.

Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA. The reactivation of telomerase activity by aberrant upregulation/expression of its catalytic subunit hTERT is a major pathway in human tumorigenesis. However, regulatory mechanisms that control hTERT expression are largely unknown.

Human chromosome 5 carries a transcriptional regulator of human telomerase reverse transcriptase (hTERT).

Telomerase activation is crucial for cells that tend to be immortalized. Increased telomerase activity is correlated with upregulation of telomerase reverse transcriptase (TERT) expression. In most human somatic cells, hTERT expression is suppressed by multiple factors.