Despite
the wealth of knowledge gained about intrinsically disordered
proteins (IDPs) since their discovery, there are several aspects that
remain unexplored and, hence, poorly understood. A living cell is
a complex adaptive system that can be described as a wetwarea
metaphor used to describe the cell as a computer comprising both hardware
and software and attuned to logic gatescapable of “making”
decisions. In this focused Review, we discuss how IDPs, as critical
components of the wetware, influence cell-fate decisions by wiring
protein interaction networks to keep them minimally frustrated. Because
IDPs lie between order and chaos, we explore the possibility that
they can be modeled as attractors. Further, we discuss how the conformational
dynamics of IDPs manifests itself as conformational noise, which can
potentially amplify transcriptional noise to stochastically switch
cellular phenotypes. Finally, we explore the potential role of IDPs
in prebiotic evolution, in forming proteinaceous membrane-less organelles,
in the origin of multicellularity, and in protein conformation-based
transgenerational inheritance of acquired characteristics. Together,
these ideas provide a new conceptual framework to discern how IDPs
may perform critical biological functions despite their lack of structure.
Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation, which leads to deregulated expression of the cell cycle regulatory protein cyclin D1 (CCND1). Genomic studies of MCL have also identified recurrent mutations in the coding region of CCND1. However, the functional consequence of these mutations is not known. Here, we showed that, compared to wild type (WT), single E36K, Y44D or C47S CCND1 mutations increased CCND1 protein levels in MCL cell lines. Mechanistically, these mutations stabilized CCND1 protein through attenuation of threonine-286 phosphorylation, which is important for proteolysis through the ubiquitin-proteasome pathway. In addition, the mutant proteins preferentially localized to the nucleus. Interestingly, forced expression of WT or mutant CCND1 increased resistance of MCL cell lines to ibrutinib, an FDA-approved Bruton tyrosine kinase inhibitor for MCL treatment. The Y44D mutant sustained the resistance to ibrutinib even at supraphysiologic concentrations (5–10 μM). Furthermore, primary MCL tumors with CCND1 mutations also expressed stable CCND1 protein and were resistant to ibrutinib. These findings uncover a new mechanism that is critical for the regulation of CCND1 protein levels, and is directly relevant to primary ibrutinib resistance in MCL.
Summary
Tumor heterogeneity and cisplatin resistance are major causes of tumor relapse and poor survival. Here, we show that in lung cancer, interaction between paxillin (PXN) and integrin β4 (ITGB4), components of the focal adhesion (FA) complex, contributes to cisplatin resistance. Knocking down PXN and ITGB4 attenuated cell growth and improved cisplatin sensitivity, both in 2D and 3D cultures. PXN and ITGB4 independently regulated expression of several genes. In addition, they also regulated expression of common genes including USP1 and VDAC1, which are required for maintaining genomic stability and mitochondrial function, respectively. Mathematical modeling suggested that bistability could lead to stochastic phenotypic switching between cisplatin-sensitive and resistant states in these cells. Consistently, purified subpopulations of sensitive and resistant cells re-created the mixed parental population when cultured separately. Altogether, these data point to an unexpected role of the FA complex in cisplatin resistance and highlight a novel non-genetic mechanism.
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