C-terminally truncated form of αB-crystallin is associated with IDH1 R132H mutation in anaplastic astrocytoma

Abstract

Malignant gliomas are the most common human primary brain tumors. Point mutation of amino acid arginine 132 to histidine (R132H) in the IDH1 protein leads to an enzymatic gain-of-function and is thought to promote gliomagenesis. Little is known about the downstream effects of the IDH1 mutation on protein expression and how and whether changes in protein expression are involved in tumor formation or propagation. In the current study, we used 2D DIGE (difference gel electrophoresis) and mass spectrometry to analyze differences in protein expression between IDH1(R132H) mutant and wild type anaplastic (grade III) astrocytoma from human brain cancer tissues. We show that expression levels of many proteins are altered in IDH1(R132H) mutant anaplastic astrocytoma. Some of the most over-expressed proteins in the mutants include several forms of αB-crystallin, a small heat-shock and anti-apoptotic protein. αB-crystallin proteins are elevated up to 22-fold in IDH1(R132H) mutant tumors, and αB-crystallin expression appears to be controlled at the post-translational level. We identified the most abundant form of αB-crystallin as a low molecular weight species that is C-terminally truncated. We also found that overexpression of αB-crystallin can be induced by transfecting U251 human glioblastoma cell lines with the IDH1(R132H) mutation. In conclusion, the association of a C-terminally truncated form of αB-crystallin protein with the IDH1(R132H) mutation is a novel finding that could impact apoptosis and stress response in IDH1 mutant glioma.

αB-crystallin as a promising target in pathological conditions – A review

“…A novel C-terminal truncated form of αB-crystallin was identified as being highly expressed only in mutant astrocytomas. This finding establishes the role of αB-crystallin in gliomagenesis, but there is a need for further research to verify how exactly IDH1 mutation affects this process [72].…”

“…Its expression was found in glia and neurons, and its overexpression was detected in certain cell types at pathophysiological conditions. αB-crystallin is said to be associated with the disease-causing protein aggregates, thus its connection with such neurological disturbances as anaplastic astrocytoma, Parkinson disease, aging deficits in the peripheral nervous system and multiple sclerosis [71][72][73][74][75].…”

αB-crystallin: Portrait of a malignant chaperone as a cancer therapeutic target

“…In malignant glioblastomas, the Bcl2L12 oncogene on chromosome 19q13 is highly expressed and induces robust expression of αB-crystallin protein by mechanisms that have not been elucidated (Stegh et al, 2007, 2008). Moreover, an oncogenic mutation in the tricarboxylic acid cycle enzyme isocitrate dehydrogenase-1 (R132H) that is commonly observed in gliomas drives enhanced αB-crystallin gene and protein expression (Avliyakulov et al, 2014). In contrast, inactivating mutations of the tuberous sclerosis tumor suppressor genes ( Tsc1 or Tsc2 ), increase αB-crystallin gene and protein expression by an mTORC2- and NFκB-dependent mechanism (Wang et al, 2014).…”

<p>Progression of the role of CRYAB in signaling pathways and cancers</p>

“…Only 40–50% will survive 5 years, making this the fifth-most frequent malignant cancer worldwide 113. Regarding brain cancer, high expression levels of CRYAB are evident in invasive gliomas 114,115. The higher expression of CRYAB may lead to prolonged survival of head and neck squamous cell carcinoma cells under hypoxic conditions, more likely by ROS formation 116.…”