Retinoblastoma is a childhood retinal tumor usually affecting
children one to two years of age. Although rare, it is the most common
malignant tumor of the eye in children and, left untreated,
retinoblastoma can be fatal or result in blindness.
It has also played a
special role in understanding cancer, because retinoblastomas have been
found to develop in response to the mutation and loss of a single gene -
the RB1 gene.
‘The MDM2 oncogene plays a critical role in promoting expression of the MYCN oncogene that is required for growth and survival of retinoblastoma cells.’
Researchers at The Saban Research Institute of Children's Hospital
Los Angeles have identified an unsuspected and critical role of the MDM2
oncogene in promoting expression of the MYCN oncogene that is required
for growth and survival of retinoblastoma cells. Their results are
published in the online edition of the Nature journal Oncogene
Previous studies in the lab of principal investigator David
Cobrinik of The Vision Center and Division of Ophthalmology at
Children's Hospital Los Angeles, uncovered that human retinoblastoma
arises from cone cells. This study looked at characteristics that make
these cells prone to retinoblastoma when RB1 is inactivated, allowing
unchecked cell proliferation.
"An important way in which cone cells differ from other retinal cell
types is their high expression of MDM2 and MYCN," said first author
Donglai Qi, a post-doctoral researcher in the Cobrinik lab. "We
have shown crosstalk between these two oncoproteins in which MDM2
promotes MYCN expression in retinoblastoma cells."
MDM2 is considered to be an oncogene (cancer-promoting gene) because
it can contribute to the transformation of a normal cell into a cancer
cell. Until recently, MDM2 was thought to do this mainly by inhibiting a
tumor suppressor protein, p53, which causes aberrantly proliferating
cells to undergo apoptosis. However, MDM2 also plays key p53-independent
roles in different signaling pathways, and the researchers found that
one such role is especially important in retinoblastoma.
The protein which MDM2 was found to regulate, MYCN, also plays an
important role in cell proliferation. In addition to its presence in
retinoblastoma, MYCN is amplified in 20 to 25% of neuroblastoma
tumors, and correlates with advanced disease and poor prognosis. It
also plays a role in other childhood cancers, such as medulloblastoma,
making MYCN a potentially important therapeutic target.
However, because MYCN has been especially difficult to block using
small molecules, the CHLA researchers' next step will be to look for
ways to target the mechanism through which MDM2 regulates MYCN
"This identification of a critical and unexpected node in the
retinoblastoma signaling circuitry could theoretically lead to
pharmacologic targeting," says Cobrinik, who is also with the Roski Eye
Institute, Departments of Ophthalmology and Biochemistry & Molecular
Medicine, and Norris Comprehensive Cancer Center at Keck School of
Medicine of the University of Southern California.
The study also answers a longstanding debate among researchers of
whether human retinoblastoma is more dependent upon MDM2 or its family
member MDM4, for the first time showing that it is MDM2 and not MDM4
that plays the critical role in tumor growth.