New Understanding of Retinoblastoma Proteins’ Role in Cell Death and Cancer – Retinoblastoma proteins and cell fate control: not just an old tale retold

Retinoblastoma protein RB1, which is named after a form of pediatric tumor of the eye, is among the most common genetically regulated cellular proteins to malfunction in human cancer. RB1 was also the first tumor suppressor gene to be identified and its modes of inactivation in retinoblastoma tumors provided the basis for the ground-breaking two-hit hypothesis by the geneticist Alfred G. Knudson in the 70s, according to which cancer is due to the accumulation of multiple ‘hits’ or mutations in certain genes.

Since its discovery in 1986, RB1 has emerged as a crucial cell cycle regulator able to restrain cell proliferation through the binding of transcriptional factors necessary for a cell to progress throughout its life cycle. Although many molecular mechanisms underlying RB1 regulation have been unraveled, research on this key protein has been hampered by different issues. First, RB1 belongs to a family of proteins, including RBL1/p107 and RBL2/p130, which have both specific as well overlapping functions and therefore are capable of compensating for each other’s loss, making it more difficult to dissect specific roles. Moreover, beyond cell proliferation regulation, RB family proteins are involved in many other cellular processes which can all affect cancerogenesis and RB function often depends on the context and the complex interplay with other interactors or regulatory factors.

A review article published on the journal Oncotarget, provides an in depth survey of the studies focusing on RB role in apoptosis. Apoptosis, which is a type of ‘programmed’ cell death, is a major process in cancer research: tumor cells’ ability to evade apoptosis is a hallmark of cancer and most therapeutic strategies are aimed at inducing apoptosis specifically in cancer cells. However, despite the myriad of studies, RB role in apoptosis is still controversial. The authors provide a comprehensive overview on the role of RB proteins in the coordinated control of cell decisions between either proliferation, or cell death through apoptosis. The authors also analyze, in light of recent findings, the different effects triggered by either RB loss (in terms of protein deficiency), or RB deregulation due to protein modifications, reconciling previous inconsistencies.

Although RB family proteins’ role as cellular guardians against unscheduled proliferation is well established, the clinical translation of approaches aimed at exploiting RB knowledge for diagnostic, prognostic or therapeutic purposes in the cancer setting has been difficult to achieve.

“In the era of molecular targeted therapy, more effort should be put into developing clinical knowledge of RB1 and exploiting it both as a predictive marker, and for therapeutic purposes,” says Dr. Paola Indovina, first author of the article which is signed as corresponding author by Antonio Giordano, Director and Founder of the Sbarro Health Research Organization at  Temple University  in Philadelphia, PA (www.shro.org) and Professor of Pathology and Oncology at the University of Siena, Italy, who discovered RBL2/p130 in 1993 as well as other cell cycle regulators and devoted his career to the study of cell cycle dysregulation in cancer.

Journal Reference:

  1. Indovina, F. Pentimalli, N. Casini, I. Vocca, A. Giordano. RB1 dual role in proliferation and apoptosis: cell fate control and implications for cancer therapyOncotarget, 2015. link:http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=4286&path%5B%5D=10328

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