Abstract
Cycline-dependent kinase 4 (CDK4), an enzyme of the cycline dependent or Ser/Thr protein kinase family, plays a role in cell cycle progression (G1 phase) by phosphorylating a tumor suppressor protein called pRB. Alteration of this enzyme due to missense mutation/ nonsynonymous single nucleotide polymorphisms (nsSNPs) are responsible for various types of cancer progression, e.g. melanoma, lung cancer, and breast cancer. Hence, this study is designed to identify the malignant missense mutation of CDK4 from the single nucleotide polymorphism database (dbSNP) by incorporating computational algorithms. Out of 239 nsSNPs; G15S, D140Y and D140H were predicted to be highly malignant variants which may have a devastating impact on protein structure or function. We also found defective binding motif of these three mutants with the CDK4 inhibitor ribociclib and ATP. However, by incorporating molecular dynamic simulation, our study concludes that the superiority of G15S than the other two mutants (D140Y and D140H) in destabilizing proteins nature.
Highlights
Melanoma, malignant melanoma, is a form of skin cancer caused by pigment-producing cells called melanocytes
The interference of the Cycline-dependent kinase 4 (CDK4) gene in tumor progression was disclosed by the observations that repression of CDK4 can contribute to terminal differentiation of erythroleukemia cells, whereas overexpression of CDK4 leads to tumorigenesis of different assortment of cancers inluding glioblastomas and sarcomas, lung cancer, and breast cancers [4,5,6,7]
The dbSNP database with CDK4 reported total 2118 SNPs where 852 were found in the intronic region, 239 are nonsynonymous single nucleotide polymorphisms (nsSNPs), 152 are synonymous, and the rest belongs to other categories
Summary
Malignant melanoma, is a form of skin cancer caused by pigment-producing cells called melanocytes. The etiology of the disease is fully complex including different types of genomic alteration in some genes, e.g. MC1R, CDKN2A, and CDK4, nonfunctional CDK4 is the cardinal hallmark of the disease cutaneous malignant melanoma-3 (CMM3). A vast majority of human tumors are believed to be occurred due to the deregulation of the CDK4/6–cyclin D–INK4–RB pathway [1,2,3]. The interference of the CDK4 gene in tumor progression was disclosed by the observations that repression of CDK4 can contribute to terminal differentiation of erythroleukemia cells, whereas overexpression of CDK4 leads to tumorigenesis of different assortment of cancers inluding glioblastomas and sarcomas, lung cancer, and breast cancers [4,5,6,7]. Germline mutations in the CDK4 are quite rare, having recently been discovered in families of hereditary malignant
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
