Figure 1
Genes and proteins involved in the development of malignant mesothelioma.
The p16INK4a protein activates the retinoblastoma protein (pRb) pathway, and
the p14ARF protein modulates p53. The NF2 gene encodes the merlin protein,
which acts as an upstream regulator of the Hippo pathway. The BAP1 gene encodes
BRCA1 associated protein-1, which plays a role in DNA damage response and cell
cycle control. The PTEN gene encodes the PTEN protein, which is an important
negative regulator of the PI3K/Akt pathway. The p53 protein plays a key role in
apoptosis control and cellular senescence.
Figure 2
The PTEN protein protects p53 from degradation by inhibiting the
migration of murine double minute 2 protein (MDM2) to the nucleus. There is
a cross-talk mechanism between PTEN and p53. The association between
complete loss of PTEN and a wild-type TP53 results in a senescence mechanism
designated PTEN loss-induced cellular senescence (PICS), which is an
important mechanism against malignant growth. The loss of PTEN in a cellular
context with a mutant TP53 results in prostate cancer that is more
aggressive and leukemia, both mechanisms having been demonstrated in
animals.
Figure 3
Biochemical pathways most commonly altered in malignant mesothelioma. In a,
receptor tyrosine kinases are frequently activated in malignant mesothelioma,
thus increasing the Ras and PI3K pathways. The Ras pathway activates the Raf
pathway, which phosphorylates mitogen-activated protein kinase kinase (MEK). In
turn, MEK phosphorylates mitogen-activated protein kinase (MAPK), which
migrates to the nucleus, thus regulating gene expression. In b, the Wnt pathway
controls various cellular processes. In the presence of a Wnt ligand, a complex
involving disheveled homolog (Dvl), Axin, frizzled (Fz), and low-density
lipoprotein receptor-related proteins (LRP5/6), it leads to inhibition of
ß-catenin phosphorylation and degradation. Consequently, ß-catenin migrates to
the nucleus, where it interacts with the Tcf/Lef complex, thus leading to the
activation of Wnt-responsive genes. In c, the merlin protein is encoded by the
NF2 gene and inhibits the PI3K pathway and mTOR, acting as an upstream
regulator of the Hippo pathway. A biochemical cascade is initiated by a
stimulus, macrophage stimulating 1/2 (MST1/2) phosphorylating salvador homolog
1 (SAV1), large tumor suppressor 1/2 (LATS1/2), and Mps one binder kinase 1
(MOB1). The MST1/2 and SAV1 complex phosphorylates LATS1/2; the LATS1/2 and
MOB1 complex interacts directly and phosphorylates YAP/TAZ. Phosphorylated
YAP/TAZ leads to protein degradation, whereas dephosphorylated YAP/TAZ enters
the nucleus and binds to TEAD1-4 transcription factors in order to regulate
genes involved in cell proliferation and death. In d, the PI3K/Akt/mTOR pathway
is activated by the conversion of phosphatidylinositol-3,4,5- trisphosphate
(PIP3) to phosphatidylinositol 4,5-bisphosphate (PIP2), PTEN acting as an
antagonist of this activation. PIP3, pyruvate dehydrogenase kinase, isozyme 1
(PDK1), and mammalian target of rapamycin (mTOR) phosphorylate protein kinase B
(Akt). Activated Akt participates in processes that are central to cell
proliferation, survival, and motility.
