Cdk6’s functions are critically regulated by its unique C-terminus

The vital cell cycle machinery is tightly regulated and alterations of its central signaling hubs are a hallmark of cancer. The activity of CDK6 is controlled by interaction with several partners including cyclins and INK4 proteins, which have been shown to mainly bind to the amino-terminal lobe. We analyzed the impact of CDK6's C-terminus on its functions in a leukemia model, revealing a central role in promoting proliferation. C-terminally truncated <i>Cdk6</i> (Cdk6 ΔC) shows reduced nuclear translocation and therefore chromatin interaction and fails to enhance proliferation and disease progression. The combination of proteomic analysis and protein modeling highlights that Cdk6's C-terminus is essential for protein flexibility and for its binding potential to cyclin D, p27<sup>Kip1</sup> and INK4 proteins but not cyclin B. We demonstrate that the C-terminus is a unique and essential part of the CDK6 protein, regulating interaction partner binding and therefore CDK6's functionality.

Authors

Institutions

Publication Details

Journal
iScience
Published
2024-12-27
DOI
https://doi.org/10.1016/j.isci.2024.111697
Primary Topic
Cancer Mechanisms and Therapy
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Cdk6’s functions are critically regulated by its unique C-terminus

Markus Zojer, Ulrich Stelzl, Sofie Nebenfuehr, Lisa Scheiblecker et al.
iScience
Cancer Mechanisms and Therapy
article

Cdk6’s functions are critically regulated by its unique C-terminus

Markus Zojer, Ulrich Stelzl, Sofie Nebenfuehr, Lisa Scheiblecker, Eduard Stefan, Alessia Schirripa, Karoline Kollmann, Elisabeth Gamper, Thorsten Klampfl, Valentina Kugler, Teresa Kaserer, Veronika Sexl, Iris Z. Uras, Helge Schöppe, Belinda S Maw, Huriye Ceylan
article en

Abstract

The vital cell cycle machinery is tightly regulated and alterations of its central signaling hubs are a hallmark of cancer. The activity of CDK6 is controlled by interaction with several partners including cyclins and INK4 proteins, which have been shown to mainly bind to the amino-terminal lobe. We analyzed the impact of CDK6's C-terminus on its functions in a leukemia model, revealing a central role in promoting proliferation. C-terminally truncated <i>Cdk6</i> (Cdk6 ΔC) shows reduced nuclear translocation and therefore chromatin interaction and fails to enhance proliferation and disease progression. The combination of proteomic analysis and protein modeling highlights that Cdk6's C-terminus is essential for protein flexibility and for its binding potential to cyclin D, p27<sup>Kip1</sup> and INK4 proteins but not cyclin B. We demonstrate that the C-terminus is a unique and essential part of the CDK6 protein, regulating interaction partner binding and therefore CDK6's functionality.

iScienceVol. 28(2)
University of Veterinary Medicine Vienna (AT), University of Graz (AT), Universität Innsbruck (AT), Tyrolean Cancer Research Institute (AT), BioTechMed-Graz (AT)
European Commission, Austrian Science Fund, Veterinärmedizinische Universität Wien, Universität Innsbruck, H2020 Excellent Science
Zero hunger
Openalex Percentile: Top 61%
Cancer Mechanisms and Therapy
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.