Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development?
In childhood tumors, including retinoblastoma, osteosarcoma, and neuroblastoma, the RB-E2F1 pathway is inactivated, as a rule. These tumors arise from precursor cells that fail to undergo the terminal differentiation. Noteworthy, the RB1-encoded protein (RB) does not control the cell cycle in embryo...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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Kashuba, E. Mushtaq, M. 2018-06-17T13:51:03Z 2018-06-17T13:51:03Z 2017 Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? / E. Kashuba, M. Mushtaq // Experimental Oncology. — 2017 — Т. 39, № 1. — С. 12-16. — Бібліогр.: 21 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/137599 In childhood tumors, including retinoblastoma, osteosarcoma, and neuroblastoma, the RB-E2F1 pathway is inactivated, as a rule. These tumors arise from precursor cells that fail to undergo the terminal differentiation. Noteworthy, the RB1-encoded protein (RB) does not control the cell cycle in embryonic stem cells. It has not been yet well understood how RB controls cell stemness and differentiation. The question arises why “inactive” RB is required for the survival and stemness of cells? Recently, we have found that overexpression of the RB-binding protein MRPS18-2 (S18-2) in primary fibroblasts leads to their immortalization, which is accompanied by the induction of embryonic stem cell markers and, eventually, malignant transformation. We suggest that cell stemness may be associated with high expression levels of both proteins, RB and S18-2. There must be a strict regulation of the expression levels of S18-2 and RB during embryogenesis. Disturbances in the expression of these proteins would lead to the abnormalities in development. We think that the S18-2 protein, together with the RB, plays a crucial role in the control on cell stemness and differentiation. We hope to uncover the new mechanisms of the cell fate determination. The S18-2 may serve as a new target for anticancer medicines, which will help to improve human health. We thank Professor George Klein for the fruitful discussions on the proposed hypothesis. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Point of view Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? Article published earlier |
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Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? |
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Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? Kashuba, E. Mushtaq, M. Point of view |
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Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? |
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Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? |
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Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? |
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Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? |
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do mrps18-2 and rb proteins cooperate to control cell stemness and differentiation, preventing cancer development? |
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Kashuba, E. Mushtaq, M. |
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Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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In childhood tumors, including retinoblastoma, osteosarcoma, and neuroblastoma, the RB-E2F1 pathway is inactivated, as a rule. These tumors arise from precursor cells that fail to undergo the terminal differentiation. Noteworthy, the RB1-encoded protein (RB) does not control the cell cycle in embryonic stem cells. It has not been yet well understood how RB controls cell stemness and differentiation. The question arises why “inactive” RB is required for the survival and stemness of cells? Recently, we have found that overexpression of the RB-binding protein MRPS18-2 (S18-2) in primary fibroblasts leads to their immortalization, which is accompanied by the induction of embryonic stem cell markers and, eventually, malignant transformation. We suggest that cell stemness may be associated with high expression levels of both proteins, RB and S18-2. There must be a strict regulation of the expression levels of S18-2 and RB during embryogenesis. Disturbances in the expression of these proteins would lead to the abnormalities in development. We think that the S18-2 protein, together with the RB, plays a crucial role in the control on cell stemness and differentiation. We hope to uncover the new mechanisms of the cell fate determination. The S18-2 may serve as a new target for anticancer medicines, which will help to improve human health.
|
| issn |
1812-9269 |
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https://nasplib.isofts.kiev.ua/handle/123456789/137599 |
| citation_txt |
Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? / E. Kashuba, M. Mushtaq // Experimental Oncology. — 2017 — Т. 39, № 1. — С. 12-16. — Бібліогр.: 21 назв. — англ. |
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2025-11-26T13:18:03Z |
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2025-11-26T13:18:03Z |
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1850622433024802816 |
| fulltext |
12 Experimental Oncology 39, 12–16, 2017 (March)
DO MRPS18-2 AND RB PROTEINS COOPERATE TO CONTROL
CELL STEMNESS AND DIFFERENTIATION, PREVENTING CANCER
DEVELOPMENT?
E. Kashuba1, 2, *, M. Mushtaq1
1Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm S-17177, Sweden
2R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine
In childhood tumors, including retinoblastoma, osteosarcoma, and neuroblastoma, the RB-E2F1 pathway is inactivated, as a rule.
These tumors arise from precursor cells that fail to undergo the terminal differentiation. Noteworthy, the RB1-encoded protein (RB)
does not control the cell cycle in embryonic stem cells. It has not been yet well understood how RB controls cell stemness and dif-
ferentiation. The question arises why “inactive” RB is required for the survival and stemness of cells? Recently, we have found that
overexpression of the RB-binding protein MRPS18-2 (S18-2) in primary fibroblasts leads to their immortalization, which is ac-
companied by the induction of embryonic stem cell markers and, eventually, malignant transformation. We suggest that cell stem-
ness may be associated with high expression levels of both proteins, RB and S18-2. There must be a strict regulation of the expres-
sion levels of S18-2 and RB during embryogenesis. Disturbances in the expression of these proteins would lead to the abnormalities
in development. We think that the S18-2 protein, together with the RB, plays a crucial role in the control on cell stemness and
differentiation. We hope to uncover the new mechanisms of the cell fate determination. The S18-2 may serve as a new target for
anticancer medicines, which will help to improve human health.
Key Words: mitochondrial ribosomal protein MRPS18-2, retinoblastoma protein RB, stem cells, differentiation, cancer develop-
ment, childhood tumors.
Retinoblastoma is a sporadic or hereditary child-
hood tumor that arises in the retina. Retinoblastoma
is usually diagnosed at an early age, such as before
the age of two years in cases of hereditary tumor.
The age-specific window of retinoblastoma growth
suggests that tumor formation depends on the pro-
liferation of cells transiently found in the retina (de-
veloping retina) [1]. The main genetic background
for retinoblastoma is inactivation (mostly deletions)
of the RB1 gene [2]. The RB1 gene is the first tumor
suppressor gene that was cloned and its deletion was
connected with tumor growth.
The RB1-encoded protein (RB, NP_000312)
is a phosphoprotein expressed uniformly in all tis-
sues. The RB is a major regulator of the cell cycle,
blocking entry into the S-phase by binding to E2F1.
The E2F1 (NP_005216) and several other members
of E2F family are transcription factors, which transac-
tivate genes required for the entry into the S-phase.
RB protein binds to E2F1 and inhibits the transcrip-
tional activity of the latter (Fig. 1) [3, 4]. In case of the
RB phosphorylation, the E2F1 is released from the
protein complex and performs its function. Hence,
loss of RB1 leads to uncontrolled cell proliferation.
Most probably, this explains also retinoblastoma de-
velopment.
Importantly, even if the patients with retinoblastoma
are cured, they often develop osteosarcomas and
melanomas later in life. Osteosarcomas, tumors of the
skeleton, arise from the bone-forming cells; usually
in the long bones and in the age window of 10–15 years.
Genetic conditions of osteosarcomas are similar
to retinoblastomas — mainly deletions of RB1 gene,
i.e. inactivation of the RB-E2F1 pathway [5].
Melanomas develop from the proliferating mela-
noblasts. In melanomas the RB-E2F1 pathway is also
inactivated, mainly by alterations in the INK locus
on chromosome 9 [6, 7]. This locus encodes two
proteins, CDKN2A (p16, NP_000068) and CDKN2B
(p15, NP_004927); they bind to and inhibit the
cyclin-dependent kinases CDK4 (NP_000066) and
CDK6 (NP_001138778). The CDKs phosphorylate
RB protein. It was shown that promoter regions of the
CDKN2A and CDKN2B genes are heavily methylated
in melanomas; consequently, levels of encoded proteins
drop dramatically. Phosphorylation of RB is not inhibited
then, resulting in the S-phase progression (see Fig. 1).
Noteworthy, the E2F1-RB pathway is not functional
also in one of the most dangerous childhood tumors,
neuroblastoma. Neuroblastoma, sometimes called
the embryonic tumor, arises from proliferating neuro-
blasts. It was shown that the MYCN (NP_001280157)
protein is overexpressed in neuroblastomas. MYCN
induces transactivation of the ID2 gene. As a result, the
highly expressed ID2 (NP_002157) protein competes
with the E2F1 for the binding to RB. As was described
above, the free E2F1 promotes cell division [8, 9].
Apart from the inactivation of the RB-E2F1 pathway,
and, presumably, enhanced proliferation of cancerous
cells, what are the other common features of these four
tumor types?
Actually, all of the above-mentioned tumors arise
from the partially differentiated neural crest stem cells.
Thus, retinoblastoma in the eye arises due to prolife-
ration of retinoblasts (retinal progenitor cells), which
Submitted: August 17, 2016.
*Correspondence: E-mail: Elena.Kashuba@ki.se
Tel.: +46 8 524 8 67 67
Abbreviations used: RB – RB1-encoded protein; S18-2 – RB-binding
protein MRPS18-2.
Exp Oncol 2017
39, 1, 12–16
POINT OF VIEw
Experimental Oncology 39, 12–16, 2017 (March) 13
should otherwise specialize into optical nerve cells.
In other words, the terminal differentiation of retino-
blasts is inhibited.
Fig. 1. The RB protein is a major regulator of the cell cycle.
RB blocks entry into the S-phase by binding to E2F1. The cyclin-
dependent kinases CDK4 and CDK6 phosphorylate RB, freeing the
E2F1 from a protein complex. This results in S-phase progression
Moreover, osteosarcoma results from the prolifera-
ting osteoblasts. Normally, osteoblasts should undergo
terminal differentiation into osteocytes. Melanoma cells
are the proliferating undifferentiated melanoblasts (me-
lanocyte precursors). Neuroblastoma is formed by pro-
liferating neuroblast precursor cells. Upon the normal
developmental process, the neuroblast precursor cells
are destined to differentiate into neurons or die by apop-
tosis. Hence, all these tumors arise from precursor cells
that fail to undergo the terminal stage of differentiation
(summarized in Fig. 2). What can be a reason for inhibi-
tion of differentiation, in addition to inactivation of the
RB-E2F1 pathway, supporting cell division?
Yet unexplainably, the RB protein in embryonic
stem cells is present mainly in hypo- and hyper-
phosphorylated forms, i.e. not in protein complex
with the E2F1 [10]. Hence, embryonic cell should
proliferate upon such conditions. On the other hand,
loss of RB1 leads to embryonic lethality [11]. It is still
not well understood how the RB is involved in control
on cell stemness and differentiation (see [12] for
review). A question arises why the “inactive” RB is re-
quired for the maintenance of cell stemness and nor-
mal development of a set of tissues?
We propose one of the possible explanations. Earlier,
we have shown that RB binds to the human mitochondrial
ribosomal protein MRPS18-2 (NP_054765, S18-2 in the
text). This binding prevents RB-E2F1 complex forma-
tion, thus promoting S-phase entry (Fig. 3) [13, 14].
Moreover, overexpression of the S18-2 protein
in primary rat embryonic fibroblasts leads to their im-
mortalization with the induction of embryonic stem cell
markers [15, 16]. Terminally differentiated primary rat
skin fibroblasts underwent cell transformation upon
ectopic expression of the S18-2 protein. The trans-
Fig. 2. Tumors arise from precursor cells that fail to undergo terminal differentiation. The migrating neural crest stem cells are shown
in black. The migrating cells differentiate upon arrival to their organ of destination: bone (the upper left panel), skin (the lower left
panel), retina (the upper right panel), and the sympathetic nervous system (the lower right panel). If the terminal differentiation
of precursor cells is blocked, the tumor arises
14 Experimental Oncology 39, 12–16, 2017 (March)
formed cells showed increased telomerase activity, cell
cycle disturbance, and chromosomal instability [17].
We concluded that the S18-2 is an oncoprotein and
might be involved in carcinogenesis. We have shown
recently that the S18-2 protein is expressed at high
levels in endometrial cancers compared to hyperplasia
and normal endometrium, along with the high level
of the free E2F1 [18].
Fig. 3. Mitochondrial ribosomal protein S18-2 binds to RB,
preventing the formation of RB-E2F1 complex, thus promoting
S-phase entry
Our findings and analysis of the published mi-
croarray data showed the elevated expression of the
S18-2 in stem and cancerous cells. Interestingly, levels
of the S18-2 are high in the EBV-transformed B-cells
and transformed fibroblasts (Fig. 4, indicated by ar-
rows). Besides this, heart, adrenal glands, and skeletal
muscles showed the high S18-2 levels. The data used
for the analyses described in Fig. 4 were obtained from
the GTEx Portal (http://www.gtexportal.org/home)
on 27/01/2017.
I n t e r e s t i n g l y , u p o n t h e a n a l y s i s
of the S18-2 expression pattern in CCLE (Cancer
cell line encyclopedia) at Broad Institute web-
site (https://portals.broadinstitute.org/ccle),
we noticed that the S18-2 expression was quite low
in cell lines derived from osteosarcomas, neuro-
blastomas, and chondrosarcomas. In melanoma
cell lines the S18-2 level was high (Fig. 5, indicated
by arrows). The data used for the analyses described
in Fig. 5 were obtained from the Broad-Novartis
CCLE portal (https://portals.broadinstitute.org/ccle)
on 27/01/2017. Noteworthy, in melanoma the RB-
E2F1 pathway is inactivated not by RB1 loss, i.e. the
RB protein is present.
Unfortunately, not much data is reported, concer-
ning the molecular mechanisms of chondrosar-
coma development. Few authors reported both,
loss of RB protein due to loss of heterozygosity
of RB1 gene [19], and also methylation of the CDKN2A
promoter [20, 21].
The discussed above leads to a hypothesis that
the RB and S18-2 proteins are involved together in the
maintenance of cell stemness. Hence, the stem cells
that could be terminally differentiated should express
both, RB and S18-2 proteins.
The downregulation of levels or inhibition of the func-
tion by binding to other proteins of one or both proteins
would lead to a failure in the differentiation of stem cells
and, eventually, tumorigenesis. There must be a strict
control on the expression of the S18-2 and RB: any
disturbance in the expression (upregulation or down-
regulation) would result in abnormal proliferation and/
or inhibition of differentiation (Fig. 6).
It is feasible to test the proposed hypothesis us-
ing, for example the RB1 knockout mouse fibroblasts
model. Another possibility is to work with a zebrafish
model to knock down S18-2. Also, the sub-lines of can-
cer cells derived from retinoblastoma, osteosarcoma,
Fig. 4. Expression profile of the S18-2 gene (Entrez Gene ID: 28973). The highest levels of the S18-2 were detected in adrenal gland,
heart and skeletal muscles, as well as in transformed fibroblasts and EBV-transformed lymphocytes (indicated with arrows). RPKM –
read per kilobase per million mapped reads, normalized to the gene length (see detailed description at http://www.gtexportal.org/home)
Experimental Oncology 39, 12–16, 2017 (March) 15
melanoma, and neuroblastoma, expressing the exo-
genous S18-2 and RB at the high levels could be gene-
rated. The differentiation potential of the obtained cells
and their tumorigenicity could be tested then.
b
a
c
Fig. 6. RB controls cell stemness and differentiation. (a)
RB controls cell stemness and differentiation, keeping the bal-
ance of these two processes. Mechanism of regulation is still
not well understood. (b) Any disturbance in the RB expression
would result in abnormal proliferation and/or inhibition of dif-
ferentiation. (c) We hypothesize that RB and S18-2 proteins
cooperate to maintain cell stemness. Hence, the stem cells
could be characterized by the high expression levels of both,
RB and S18-2 proteins. If cells loose RB (or S18-2), no termi-
nal differentiation could be achieved. This leads to the tumor
development then
Concluding, we think that the S18-2 protein, toge-
ther with the RB, plays a crucial role in the control on cell
stemness and differentiation. We hope to uncover the
new mechanisms of the cell fate determination. The
S18-2 may probably serve as a new target for anticancer
medicines, which will help to improve human health.
ACkNOwLEDGMENTS
We thank Professor George Klein for the fruitful
discussions on the proposed hypothesis.
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