Proteomic analysis of the human cyclin-dependent kinase family reveals a novel CDK5 complex involved in cell growth and migration.

Cyclin-dependent kinases (CDKs) are the catalytic subunits of a family of mammalian heterodimeric serine/threonine kinases that play critical roles in the control of cell-cycle progression, transcription, and neuronal functions. However, the functions, substrates, and regulation of many CDKs are poorly understood. To systematically investigate these features of CDKs, we conducted a proteomic analysis of the CDK family and identified their associated protein complexes in two different cell lines using a modified SAINT (Significance Analysis of INTeractome) method. The mass spectrometry data were deposited to ProteomeXchange with identifier PXD000593 and DOI 10.6019/PXD000593. We identified 753 high-confidence candidate interaction proteins (HCIPs) in HEK293T cells and 352 HCIPs in MCF10A cells. We subsequently focused on a neuron-specific CDK, CDK5, and uncovered two novel CDK5-binding partners, KIAA0528 and fibroblast growth factor (acidic) intracellular binding protein (FIBP), in non-neuronal cells. We showed that these three proteins form a stable complex, with KIAA0528 and FIBP being required for the assembly and stability of the complex. Furthermore, CDK5-, KIAA0528-, or FIBP-depleted breast cancer cells displayed impaired proliferation and decreased migration, suggesting that this complex is required for cell growth and migration in non-neural cells. Our study uncovers new aspects of CDK functions, which provide direction for further investigation of these critical protein kinases.

Regulation of hormonal therapy resistance by cell cycle machinery.

Estrogen Receptor (ER) plays a central role in the development and progression of breast cancer. Hormonal therapy substantially improves disease-free survival of ER+ve breast tumors, however acquired resistance to endocrine therapies frequently occur. Emerging data implicate growth factor signaling pathways and their cross talk with ER as major cause of resistance. Both these pathways have been recently shown to use cell cycle machinery as downstream effectors in mediating therapy resistance. Several studies have demonstrated deregulation of cell cycle regulators and their cross talk with ER in therapy resistant tumors. The objective of this article is to review the underlying mechanisms by which tumor cells use cell cycle machinery to override hormonal therapy and to explore cell cycle machinery components as novel therapy targets for overcoming hormonal therapy resistance.