Biomedical Engineering Reference
In-Depth Information
2001
; Stoneley and Willis
2004
). Two tumor suppressors, which regulate cell cycle
(p53 and p27) and differentiation (p27), are deregulated in primary
Dkc1
m
mouse
and X-DC patient cells. Several studies have highlighted the importance of p53 in
controlling cell quiescence and proliferation, key features of hematopoietic stem
cells (HSCs) and lineage-committed hematopoietic cells (Kastan et al.
1991
; Liu
et al.
2009
; Okazuka et al.
2005
; Shaulsky et al.
1991
; Slatter et al.
2010
) . Both cell
types are essential for the production of mature blood cells and when deregulated
may contribute to BMF. Additionally, p27 regulates multiple aspects of hematopoi-
esis. Specifically, in vivo studies demonstrate that p27 is important for maintaining
quiescence, controlling the number of hematopoietic progenitor cells, and restrict-
ing the proliferative capacity of naïve CD8+ T cells (Tsukiyama et al.
2001
;
Wolfraim and Letterio
2005
). Collectively, these findings provide strong evidence
that deregulations in IRES-dependent translation of both p53 and p27 may contrib-
ute to many aspects of BMF, the primary cause of X-DC patient lethality.
In addition, defective IRES-dependent translation in primary X-DC patient cells
may provide a possible functional explanation for the increased cancer susceptibil-
ity in X-DC. Dyskerin and rRNA pseudouridylation play an important role in a
specific translational switch between cap- and IRES-mediated translation that
occurs during oncogene-induced senescence (OIS) (Bellodi et al.
2010a
) , which is
one of the first tumor suppressive barriers that restrict cancer progression (Serrano
et al.
1997
). This translational switch allows the expression of specific mRNAs,
such as the tumor suppressor p53, which is necessary and sufficient to promote OIS.
Importantly, during this switch, p53 IRES-mediated translation is significantly
impaired in the absence of adequate rRNA pseudouridylation, rendering
Dkc1
m
mouse cells more susceptible to oncogenic transformation (Bellodi et al.
2010a
) .
A role for rRNA modification defects in tumorigenesis is also supported by findings
that reductions in dyskerin levels are associated with downregulation of p53 protein
levels and activity in human breast cancer cells (Montanaro et al.
2010
) . Furthermore,
a novel point mutation in DKC1 that is associated with reduced levels of rRNA
pseudouridylation has recently been identified in a pituitary cancer patient.
Interestingly, in this pituitary tumor, decreased dyskerin activity correlates with a
reduction in p27 protein expression at the posttranscriptional level (Bellodi et al.
2010b
). Collectively, these findings have provided functional insights into how
impairments in rRNA pseudouridylation contribute to highly specific translation
defects that may contribute, at least in part, to the increased cancer susceptibility
observed in X-DC patients as well as patients harboring DKC1 somatic
mutations.
Consistent with findings that ablation of dyskerin expression is detrimental to life
(Sect.
13.4.2
), it is not surprising that two mutations found in the catalytic domain
of the gene encoding dyskerin are associated with a severe variant of X-DC known
as Hoyeraal-Hreidarsson syndrome (HHS), an exceedingly rare condition character-
ized by growth retardation, microcephaly, cerebellar hypoplasia, and aplastic ane-
mia (Hoyeraal et al.
1970
; Hreidarsson et al.
1988
; Yaghmai et al.
2000
) . The severe
clinical phenotypes observed in HHS may result from a decrease in global protein
synthesis due to a more acute inactivation of dyskerin catalytic activity. The genetic
lesions underlying more than 50 % of DC cases remain unknown, and it will be
Search WWH ::
Custom Search