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Zhu et al. Function of Mcl-1 and its regulative relations with HCC

kinase contributed to phosphorylation of Thr 163 and Mcl-1 and then CDK1 and CDK2, proteins related to
Serine 121 of Mcl-1, prolonged the half-life of the Mcl- cell cycle, and JNK were affirmed to phosphorylate
1 protein and protected hepatocytes against apoptosis this residue, which plays a negatively role on the
induced by tumor necrosis factor alpha (TNFα). And progression of apoptosis. Moreover, it was reported
data from Wang et al. [73] demonstrated that the Bcl-2/ that both protein and mRNA levels of Mcl-1 were
xL inhibitor ABT-263 increased Mcl-1 stability in HCC down-regulated by a novel synthetic CDK inhibitor
cells while activation of ERK and JNK involved in ibulocydine in HCC cells. [84]
ABT-263-mediated Mcl-1 protein stabilization through
phosphorylation of Mcl-1 Thr163. And also it has Another protein impacting Mcl-1’s roles in cell cycle
been reported that the new tubulin inhibitor MT189 is PCNA. It has been mentioned before that Mcl-1
(2-(6-fluoro-3-((4-methoxybenzyl)amino) imidazo [1,2- can bind to PCNA and CDK1 in the nucleus, which
α] pyridin-2-yl) phenol)-mediated JNK activation participate in repression of cell cycle progression.
caused degradation of Mcl-1 protein via facilitating its When transfection of Huh7 and HepG2 cells with
phosphorylation in the SMMC-7721 cells. [74] glypican 3-specific siRNA, cell proliferation detected
by PCNA immunohistochemistry was inhibited, cell
Glycogen synthase kinase-3 (GSK-3) inactivated by cycle was arrested at the G1 phase and anti-apoptotic
Akt plays a crucial role in the regulation of apoptosis. proteins (Bcl-2, Bcl-xL, and Mcl-1) were down-
It has been demonstrated that the control of Mcl- regulated. [85] Besides, different from other reports
1 stability by GSK-3 is an important mechanism for about interaction between PCNA and the Mcl-1 or the
the regulation of apoptosis by growth factors, PI3K, CDK2 protein in biochemical assays, De Biasio et al. [31]
and Akt. [75] Deeper research indicated that GSK- detected no binding between them and suggested that
3 was conducive to degradation of Mcl-1 by means the interaction, if any, occurs with very low affinity or is
of phosphorylation of its Serine 155 and Serine 159 mediated by other factors. Lately, a report described
and the latter inhibited the interaction of Mcl-1 with that following the inhibition of RNA polymerase II
the pro-apoptotic protein, Bim, thus impairing its anti- phosphorylation, ibulocydine caused down-regulation
apoptotic function. [75,76] What’s more, Wang et al. [73] of Mcl-1, survivin, and X-linked inhibitor of apoptosis
[84]
indicated that Akt-mediated GSK-3β inactivation also protein (XIAP), thus inducing apoptosis in HCC cells.
implicated in ABT-263-induced Mcl-1 stabilization,
possibly through regulating the phosphorylation of Owing to the extremely labile nature of Mcl-1, it is as
Mcl-1 Ser159 in HCC cells. important as those that regulate Mcl-1 synthesis for
cellular processes to regulate Mcl-1 stability. Recently,
Mcl-1 interacting proteins a Mcl-1 interacting protein the translationally controlled
tumor protein (TCTP) was identified to upregulate the
The majority of proteins interacting with Mcl-1 belong expression levels of Mcl-1 through modulating Mcl-1
to the Bcl-2 protein family including multidomain pro- stability and eventually modulate Mcl-1’s antiapoptotic
apoptotic members and the BH3-only proteins. [77-79] In activity by the ubiquitin-dependent proteasome
this review, we just discuss other proteins interacting degradation pathway. Detailed analysis revealed
with Mcl-1. The Mcl-1 protein level can be downregulated that TCTP overexpression inhibited apoptosis by
by adenovirus infection through proteasome-mediated binding to Mcl-1 and antagonizing Bax. [86] It has been
turnover of Mcl-1. [80] Mcl-1 ubiquitin ligase E3 (Mule) well documented that TCTP was implicated in many
contains a region similar to BH3 domain that enables cellular functions including human allergic response, [87]
Mule to interact with Mcl-1. It has been demonstrated apoptosis [88] and cell growth. [89] Chen et al. [90] described
that Mule was required for the polyubiquitination of Mcl- that Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional
1 in the ubiquitin dependent proteasome degradation medicinal prescription, could downregulate the protein
pathway. [81] According to a research treatment of expression level of Mcl-1 and TCTP in Hep-G2 cells,
HepG2 cells with glycochenodeoxycholate (GCDA), thus they considered that decreasing TCTP and Mcl-1
one of the major human bile salts, the author reported expression may be one of the molecular mechanisms
that GCDA facilitated Mcl-1 dissociation from E3 ligase by which SJKJT inhibits Hep-G2 cells. It has also
Mule and increased the half-life of Mcl-1. [82] been reported that curcumin inhibited the proliferation
of human HCC J5 cells and induced mitochondrial
Cyclin-dependent kinase (CDK) could combine and dysfunction by decreasing the expressions of TCTP,
activate cyclin, and thus lead to phosphorylation Mcl-1 and Bcl-2. [91] Similarly, after treatment of HCC
of target protein. The phosphoresidue serine 64 of SK-Hep-1 cells with ursolic acid, the western blot
Mcl-1 was identified by Kobayashi et al. [83] through results were associated with decreased expression of
MS analysis of a threonine 163 to alanine mutant of Mcl-1, TCTP and Bcl-2. [54]

134 Hepatoma Research ¦ Volume 3 ¦ July 06, 2017