JOINT SEMINAR
NATIONAL CENTRE FOR BIOLOGICAL SCIENCES TIFR, BANGALORE
AND
CENTRE FOR HUMAN GENETICS, BANGALORE
Date : Thursday, February 26, 2015
Time : 2:00pm
Speaker: Dr. Suresh C. Jhanwar
Memorial Sloan-Kettering Cancer Center
New York, USA
Title : Cell origin, Trb2-Skp2 signaling, and Skp2 targeted therapy in
human retinoblastoma
Venue : Malgova (70 Seater)
Host : Dr. Sudhir Krishna (skrishna@ncbs.res.in)
Dr. Reety Arora (reetya@instem.res.in)
Abstract:
Retinoblastomas initiate in response to biallelic RB1 inactivation and loss of functional Rb protein, yet the cell of origin and cellular circuitry that sensitizes to Rb loss have been unclear. Here, we assessed the responses to shRNA-mediated Rb depletion in dissociated fetal retinal cells, in intact retina, and in isolated cone precursor populations. In dissociated retinal cultures, RB1 knockdown induced S phase entry and proliferation of cells expressing markers of cone precursors (CRX + L/M opsin, or CRX + cone arrestin, or CRX + RXRγ) but not markers or other retinal cell types. Similarly, RB1 knockdown induced cone precursor proliferation in the undissociated retina and in prospectively isolated cone precursor populations. Proliferation of FACS-isolated cone precursors correlated with the induction of E2F-responsive genes and depended upon factors having strong cone precursor expression and crucial roles in retinoblastoma cell proliferation, including MDM2, MYCN, TRβ2, and SKP2. The proliferative response to Rb depletion was enhanced by co-depletion of the Rb-related p130, concordant with frequent p130 losses in retinoblastoma tumors. Rb- and Rb/p130-depleted cone precursors proliferated in suspension and formed tumors in orthotopicxenografts with histologic features and protein expression profiles typical of differentiated human retinoblastomas. Further studies showed that loss of RB1, resulting in loss of phospho-Rb, enables TR1-dependent suppression of SKP2, as a safeguard against RB1-deficient tumor formation. High level cone-specific TR2 counteracts TR1 to stabilize SKP2, thus disrupting this safeguard and enabling the development of RB1-deficient tumors. These findings suggest that post-mitotic human cone precursors are uniquely sensitive to the proliferative and oncogenic effects of Rb depletion and imply that human cone precursor circuitry collaborates with inactivating RB1 mutations to initiate retinoblastoma tumorigenesis. SKP2-KD caused apoptosis of retinoblastoma tumor cells, indicating that SKP2 is a synthetic lethal gene in retinoblastoma. Targeted therapy by SKP2 inhibitor C1 significantly suppressed retinoblastoma tumor growth in vitro and in vivo.
ALL ARE WELCOME
