Identifying new regulators of the stem cell state offers potential for future gains in biomedicine. Evidence that the tumor suppressor p53 is a key regulator of the stem cell state (Cicalese et al., 2009) suggests a broad role for this protein and its pathways in the control of normal tissue homeostasis and tumor formation

Aparicio, Samuel

Eaves, Connie J.

Elsevier - Publisher Connector 

or Aub localize to the 42AB and other 
dual-strand clusters. A physical interac-
tion between Piwi and HP1a has been 
observed in somatic cells of Drosophila 
(Brower-Toland et al., 2007), where Piwi 
might recruit HP1a to transcriptionally 
silence these regions. In the fly ovaries, 
Rhino may take the place of HP1 in a 
similar kind of interaction to promote 
the expression of dual-cluster RNAs 
and the generation of piRNAs to silence 
transposons. An intriguing possibility is 
that another HP1 protein, HP1e, which 
is preferentially expressed in the male 
germline (Vermaak et al., 2005), pro-
motes dual-cluster RNA expression in 
sperm. Future studies on the interplay 
between Rhino, other HP1 proteins, and 
piRNA generation should provide fur-
ther insights into this fascinating area of 
genome biology.
RefeRences
Brennecke, J., Aravin, A.A., Stark, A., Dus, M., 
Kellis, M., Sachidanandam, R., and Hannon, G.J. 
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681–692.p53: A new Kingpin in the stem cell Arena
Samuel Aparicio1,3 and Connie J. Eaves2,3,4,*
1Department of Molecular Oncology
2Terry Fox Laboratory, British Columbia Cancer Agency
3Departments of Pathology and Laboratory Medicine
4Department of Medical Genetics, University of British Columbia
Vancouver BC V5Z 1L3, Canada
*Correspondence: ceaves@bccrc.ca
DOI 10.1016/j.cell.2009.09.004
Identifying new regulators of the stem cell state offers potential for future gains in biomedicine. 
Evidence that the tumor suppressor p53 is a key regulator of the stem cell state (Cicalese et 
al., 2009) suggests a broad role for this protein and its pathways in the control of normal tissue 
homeostasis and tumor formation.“Self-renewal potential” is the usual 
answer to the topical question of what 
distinguishes stem cells from other cell 
types. Interestingly, a clear definition of 
“self” remains enigmatic. Stem cells are 
unique in their possession of a latent 
readiness to differentiate into many cell 
types that can be propagated through 
many cell divisions without being lost. 
The fact that tumors represent rare per-
turbed clonal outgrowths of normal tissue 
has led to the concept that their continu-
ous propagation may rely on an analo-
gous subset of cancer stem cells whose 
self-renewal and differentiation fate 
decisions are deregulated by mutation or 
epigenetic changes. Our understanding 
of the molecular machinery that governs 1060 Cell 138, September 18, 2009 ©2009 Ethe self-renewal behavior of both normal 
and cancer stem cells remains ephem-
eral. A recent stimulus to addressing 
this challenge has come from a growing 
expectation of major benefits for regen-
erative medicine and cancer therapy. In 
this issue of Cell, Cicalese et al. (2009) 
provide a further link between normal 
and cancer stem cells with their study of 
self-renewal divisions in a mouse model 
of breast cancer. Their study provides 
new evidence that the tumor suppres-
sor protein p53 may serve as a kingpin 
guardian of the normal stem cell state.
Many adult tissues are thought to be 
sustained by hierarchies of differentiat-
ing cells that ultimately depend on the 
balanced turnover and loss of “self” lsevier Inc.status of a specific stem cell compart-
ment. Yet, for only a few has a biologi-
cally distinct stem cell population been 
definitively identified. The hematopoietic 
system was one of the first of these and 
has served as a paradigm for subse-
quent analyses of other tissues, includ-
ing the normal mammary gland of the 
breast (Shackleton et al., 2006; Stingl et 
al., 2006).
Stem cells can execute either a sym-
metric or asymmetric self-renewal divi-
sion, thereby giving rise to either two 
daughter stem cells or one daughter 
stem cell plus one that is destined to 
differentiate within a few cell divisions. 
A favored mechanism for the acquisi-
tion of functional asymmetry by the 
two daughter cells is the acquisition of 
physical asymmetry during cell division. 
Notable candidates that may be asym-
metrically distributed include mRNA 
transcripts or other cytoplasmic com-
ponents such as the Notch, Numb, and 
Par proteins. Potential consequences 
of cell stress or genome damage on cell 
division outcomes have been less well 
explored. Recently, five different labo-
ratories independently identified p53 as 
an important checkpoint during the mul-
tifactor  reprogramming process in which 
induced pluripotent stem (iPS) cells are 
derived from differentiated adult cells 
(Hong et al., 2009; Kawamura et al., 
2009; Li et al., 2009; Marion et al., 2009; 
Utikal et al., 2009). In each case, absence 
of functional p53 enhanced the yield of 
iPS cells, suggesting that p53 may be a 
major gatekeeper of self-renewal.
Key to delineating the properties of 
normal and cancer stem cells is the 
specificity of the method used to detect 
and measure them. For normal mam-
mary epithelial stem cells, the specificity 
is obtained by demonstrating the ability 
of a single cell to reconstitute an entire 
mammary gland structure. The prospec-
tive isolation of cells with such proper-
ties (called mammary repopulating units 
or MRUs) has now been defined for nor-
mal human (Eirew et al., 2008) as well 
as mouse mammary tissue (Shackleton 
et al., 2006; Stingl et al., 2006). In the 
mouse, highly enriched MRU-containing 
populations are obtained by removal of 
non-mammary cells (hematopoietic and 
stromal cells that heavily contaminate 
fresh breast tissue) and positive selec-
tion for cells expressing the highest 
levels of CD49f and CD29 (an integrin 
complex found on the surface of most 
basal mammary cells) as well as inter-
mediate levels of CD24. However, the 
MRU purities of these fractions are still 
insufficient (<10%) to allow meaningful 
inferences about MRUs to be made from 
direct characterization of such cell sus-
pensions.
Mammospheres are three-dimensional 
multilayered structures that form when 
disaggregated, unseparated normal 
mammary epithelial cells are cultured 
under conditions that inhibit cell attach-
ment to the culture dish surface. When 
the culture medium contains appropri-
ate supplements, primitive mammary cells capable of further proliferation and 
differentiation can be detected in these 
structures for several weeks (Dontu et al., 
2003). Terminal differentiation appears to 
be less well supported under these con-
ditions, so some apparent enrichment 
in the content of primitive cell subtypes 
is seen. These features, and the obvi-
ous practical advantages of in vitro sys-
tems for analyzing cellular events, have 
made mammosphere cultures popular 
for investigating mechanisms that regu-
late the biology of primitive mammary 
cells, as Cicalese et al. now demon-
strate. However, as these authors point 
out, mammosphere cultures also have 
notable limitations. For example, defini-
tive evidence of a clonal origin of MRUs 
from cells that generate the other cells 
present in the mammosphere has not 
yet been reported. In addition, normal 
epithelium mammosphere cultures do 
not yield net increases in either sphere-
forming cells or MRUs.
Notwithstanding these caveats, 
Cicalese et al. sought to compare the 
growth properties of normal and cancer 
stem cells in cultured mammospheres. 
The mammospheres were derived from 
the mammary tissue of wild-type mice, 
mice lacking p53, and a transgenic 
mouse model of breast cancer in which 
the cells overexpress the ERBB2 onco-
gene. They report that CD49fhiCD24+ 
cells (the putative MRU-enriched frac-
tion) in the mammary gland of mice 
lacking p53 display a much greater rep-
licative potential in mammosphere cul-
tures than do their normal counterparts. 
Moreover, they found that the frequency 
of MRUs (detected in transplantation 
assays) in mammary tissue from p53-
deficient mice was 10-fold higher than 
in wild-type mammary tissue. Taken 
together, these findings point strongly 
to a key role for p53 in the control of 
MRU compartment size. In a parallel 
series of experiments, they found that 
the sphere-forming activity of mouse 
mammary tumor cells overexpressing 
ERBB2 was perpetuated in vitro beyond 
that typical of premalignant mammary 
tissue expressing ERBB2. Although p53 
was not apparently mutated in the tumor 
cells, evidence that their p53 activity 
was reduced was shown by abrogated 
responses to DNA damage. Furthermore, 
reactivation of p53 by nutlin3 (through Cell 138, Seinhibition of MDM2) both normalized the 
sphere-forming activity of the ERBB2-
induced mammary tumor cells and con-
comitantly reduced their tumor-initiating 
activity. These results identify p53 as 
a participant in processes regulating 
malignant as well as normal epithelial 
stem cell populations.
But how does p53 regulate the stem 
cell state? One possibility, hinted at in 
the Cicalese et al. study, is that p53 may 
control whether or not a stem cell divi-
sion is asymmetric or not. This idea is 
based on the authors’ observations of 
the heterogeneous rates of dilution of 
PKH26 (a membrane intercalating dye) 
in dividing pairs of cells in early devel-
oping mammospheres. The ERBB2 
tumor cells showed predominantly 
symmetric losses of PKH26 fluores-
cence, in marked contrast to normal 
mammospheres in which an asymmet-
ric label dilution pattern was commonly 
seen. The investigators propose that 
breast cancer stem cells have a deregu-
lated ability to execute symmetric self-
renewal divisions as compared to their 
normal counterparts. Follow-up studies 
to define the functional properties of the 
daughter cells of the first and second 
divisions of these cells and to deter-
mine if and how the distribution of p53 
(or other members of the pathway) may 
be affected will be important to put the 
PKH26 data into a more precise cellular 
and molecular context. The observa-
tions of Cicalese et al. and those impli-
cating p53 in iPS cell generation beg for 
further studies to determine if and how 
this new kingpin may play a general role 
in regulating stem cell states.
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During embryogenesis, neural circuits 
are formed through the precise spatial 
and temporal production of functionally 
distinct classes of neurons by undif-
ferentiated stem and progenitor cells. 
Although significant progress has been 
made in identifying the morphogen sig-
nals that spatially organize the develop-
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served as a model for studying neuro-
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first specified by the patterning actions 
of Sonic hedgehog and retinoic acid sig-
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of the essential motor neuron determi-
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Once formed, these motor neuron pro-
genitors divide a limited number of times 
Reducing the M
Differentiation
Bennett G. Novitch1,* and Samantha J. B
1Department of Neurobiology, Broad Center of
UCLA, Los Angeles, CA 90095, USA
2Department of Biological Sciences, University
*Correspondence: bnovitch@ucla.edu (B.G.N.
DOI 10.1016/j.cell.2009.09.001
In the developing nervous syste
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phodiester phosphodiesterase domain 
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utler2,*
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), butlersj@usc.edu (S.J.B.)
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capacity to exit the cell cycle and differ-
entiate into motor neurons. Their gain-of-
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misexpression of Prdx1 alone has little 
effect on neuronal development, Prdx1 
synergistically promotes motor neu-
nal 
h, David Geffen School of Medicine at 
, USA
ell cycle and differentiate on a 
 poorly defined. Yan et al. (2009) 
ein GDE2 and the peroxiredoxin 


p53: A New Kingpin in the Stem Cell Arena 

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p53: A New Kingpin in the Stem Cell Arena

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