MTs the remediation of Bcl-2 protein expression.

MTs follow a process of
polymerization and depolymerization activated by the presence of a tyrosine
residue at the c-terminal end of MT.  Following
the removal of this tyrosine via tyrosine carboxypeptidase, MT is depolymerized
(Amaiden et al., 2015).  Another type of
tubulin modulation produces an acetylated ?-tubulin subset for which structural
modeling suggests that acetylation may stabilize lateral interactions between
neighboring tubulin protofilaments, potentially explaining the increased
stability of acetylated MTs observed in vivo (Al-Bassam et al., 2012).  Tubulin acetylation is a post-translational
modification consisting of the reversible addition of an acetyl group on the
?-amino group of Lys40 residue of ?-tubulin. 
The stabilized form of MTs has been claimed to interact directly with
the NKA receptor (Zampar et al., 2009). Therefore, NKA may function as an
anchoring site for microtubules to the plasma membrane, and vice versa, and MT
may “grab” NKA before the latter enters the escalator into the deeper realms of
the cell. This is an important finding because it allows the possibility of
‘cross-talk’ between the MT cytoskeleton architecture and dynamics, and
regulation of NKA activity (Zampar et al., 2009). 

Steroid Receptor coactivator 1 & 3 (SRC 1
& SRC 3)

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A possible outcome of
the internalization of NORC could be its lysosomal degradation, where NKA and
ouabain could be split.  Upon this split,
ouabain may interact with steroid nuclear receptors should its steroidal core
move through the endoplasmic reticulum.  This
would follow similar binding found between the cardiac glycoside bufalin and
SRC (Jin, O’Malley et al., 2014).  PL1 SJ2 Bufalin
reduces SRC-1 and SRC-3 protein expression and retards cancer cell growth in
vitro and in vivo (Zhou, 2005). 
Additional results by Zhou indicated a significant decrease of Bcl-2 protein PL3 SJ4 and
mRNA levels with the down-regulation of SRC-3. 
These data suggest that SRC-3 functions to promote cell growth and
survival through multiple mechanisms (Zhou, 2005).  If holding true for other CTS, ouabain may
interact similarly to bufalin explaining its positive attenuation of some
cancer types as well as the regulatory apoptotic mechanisms through the
remediation of Bcl-2 protein expression.

Significance

With a broad variety of
CTS to NKA interactions identified, it must be determined if these mechanisms
are functioning through an undefined process related to the internalization of
NORC.  We therefore propose a
“microtubule escalator” that may exist, or be polymerized, because of ouabain’s
interaction with NKA.  This transit network
of microtubule-assisted internalization would occur by first inhibition of Na+/K+
exchange through assembly of ouabain and NKA. 
In response to this inhibition, the embodiment of NORC via caveolin-1
assisted invagination through the plasmalemmal membrane would occur.  This invagination would then be followed by
transport from early endosome to lysosomal vesicles within the cytosol.  Lysosomal bodies could then break down NORC
to NKA for recycling to the plasmalemmal membrane, and ouabain for processing
in the endoplasmic reticulum.  Once
processed in the endoplasmic reticulum, ouabain may interact with nuclear
receptors, causing subsequent gene upregulation. Figure 1.4 represents the
current model and expected results from previous experiments of this project,
and from the literature.  Should
experimentation echo similar action to the above, further identification of
affected regulatory mechanisms would need be elucidated.  We propose NKA’s and CTS’s intracellular
actions may occur either as a complex (NORC) or by via cleavage of ouabain from
NKA, where the former could “hormonally” modulate steroidal receptor
coactivators at the nucleus.  If these
mechanisms are confirmed, their relevance for transcriptional modification need
to be identified.

 PL1Is
larionov part of O’Malley’s group?? In Texas?

 SJ2No,
it appears that O’Malley was working under the Jin group.  I have corrected the citation.

 PL3Which
Bcl2 protein?

 SJ4The
authors did not specify which Bcl-2 proteins. Per the paper the data only shows
Bcl-2 protein.