The RB family is required for the self-renewal and survival of human embryonic stem cells.

The mechanisms ensuring the long-term self-renewal of human embryonic stem cells are still only partly understood, limiting their use in cellular therapies. Here we found that increased activity of the RB cell cycle inhibitor in human embryonic stem cells induces cell cycle arrest, differentiation and cell death. Conversely, inactivation of the entire RB family (RB, p107 and p130) in human embryonic stem cells triggers G2/M arrest and cell death through functional activation of the p53 pathway and the cell cycle inhibitor p21.

A crucial requirement for Hedgehog signaling in small cell lung cancer.

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment. Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo.

Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma.

Small-cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. Although SCLC patients often initially respond to therapy, tumors nearly always recur, resulting in a 5-year survival rate of less than 10%. A mouse model has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLCs.

Keeping an eye on retinoblastoma control of human embryonic stem cells.

Human embryonic stem cells (hESCs) hold great promise in regenerative medicine. However, before the full potential of these cells is achieved, major basic biological questions need to be addressed. In particular, there are still gaps in our knowledge of the molecular mechanisms underlying the derivation of hESCs from blastocysts, the regulation of the undifferentiated, pluripotent state, and the control of differentiation into specific lineages.

Stabilization and analysis of intron lariats in vivo.

The analysis of lariats produced in vivo during pre-mRNA splicing is a powerful tool for elucidation of regulatory mechanisms and identification of natural recursive splicing events. Nevertheless, this analysis is technically challenging because lariats normally have short half-lives. With appropriate controls, RT-PCR amplification and sequencing of the region spanning the 2'-5' phosophodiester bond at the branch junction can be a sensitive and versatile method for lariat analysis.