The retinoblastoma tumor suppressor and stem cell biology

Abstract

Stem cells play a critical role during embryonic development and in the maintenance of homeostasis in adult individuals. A better understanding of stem cell biology, including embryonic and adult stem cells, will allow the scientific community to better comprehend a number of pathologies and possibly design novel approaches to treat patients with a variety of diseases. The retinoblastoma tumor suppressor RB controls the proliferation, differentiation, and survival of cells, and accumulating evidence points to a central role for RB activity in the biology of stem and progenitor cells. In some contexts, loss of RB function in stem or progenitor cells is a key event in the initiation of cancer and determines the subtype of cancer arising from these pluripotent cells by altering their fate. In other cases, RB inactivation is often not sufficient to initiate cancer but may still lead to some stem cell expansion, raising the possibility that strategies aimed at transiently inactivating RB might provide a novel way to expand functional stem cell populations. Future experiments dedicated to better understanding how RB and the RB pathway control a stem cell's decisions to divide, self-renew, or give rise to differentiated progeny may eventually increase our capacity to control these decisions to enhance regeneration or help prevent cancer development.

Figure 1.

Classical view of the RB pathway and RB function in mammalian cells. (A) Schematic representation of the canonical RB pathway. Small cell cycle inhibitors prevent the phosphorylation of RB and its family members by Cyclin/Cdk complexes. E2F transcription factors are major mediators of RB function in mammalian cells. (B) Examples of RB's mode of action in cells to restrain cell cycle progression and promote differentiation. (Top) Classically, RB binds to the regulatory regions of cell cycle genes via its interaction with E2F transcription factors and recruits repressor complexes to inhibit the expression of cell cycle genes. (Second from top) RB also controls the cell cycle by blocking the degradation of the p27 small cell cycle inhibitor (of the p21 family) by Skp2; high p27 levels can directly inhibit Cdk2 kinase activity and slow cell cycle progression. (Third from top) RB can promote differentiation in cooperation with other transcription factors, such as Runx2, in the bone lineage. (Bottom) RB can also control cell fate by controlling the expression of transcription factors involved in cellular differentiation, such as PPARγ during adipogenesis.

Figure 2.

RB function in adult stem cells. Simplified view of an RB wild-type adult organ, with quiescent populations of stem cells (SCs) giving rise to proliferating progenitor cells (PCs) that can exit the cell cycle to generate differentiated cells (DC) and terminally differentiated cells (TDCs). In an RB mutant (or RB family mutant) context, exit from quiescence and increased numbers are often observed in stem cell populations, and increased proliferation is often present in progenitor cells. In some cases, this increased proliferation is accompanied by increased cell death, especially as progenitors are induced to enter a differentiation program. Loss of RB also leads to a reduced capacity to differentiate and terminally differentiate in some lineages. Finally, RB inactivation may favor certain cellular fates by default (no death and no decrease in differentiation potential) or actively (by activation of a program of genes); however, loss of RB often prevents terminal differentiation. Eventually, although stem cells and progenitor cells may be the cell populations that are initially responsive to loss of RB in adult tissues and organs, tumors initiated by loss of RB may be mostly composed of cells with differentiated characteristics (“differentiated cancer”).

Figure 3.

RB function in ES and iPS cells. (A) It is thought that RB and its family members are largely inactivated by hyperphosphorylation due to high Cyclin/Cdk activity in mouse and human ES cells, allowing these cells to self-renew and expand. Proper regulation of RB activity may also be crucial to maintain genomic stability. When ES cells are induced to differentiate, a simple model would be that reduced Cdk activity leads to increased RB activity, which in turn promotes cell cycle exit and differentiation. It is also possible that changes in RB and E2F activity in response to stress control the ability of ES cells to undergo cell death. (B) Emerging evidence suggests that RB activity gradually declines during the reprogramming of differentiated cells into iPS cells, as these cells “dedifferentiate” and acquire the capacity to proliferate indefinitely.