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Molecules. 2018 Jun 15;23(6). pii: E1454. doi: 10.3390/molecules23061454.

Phosphoproteomics of Retinoblastoma: A Pilot Study Identifies Aberrant Kinases.

Author information

1
L&T Opthalmic Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India. lakshmi.nagarajhan@gmail.com.
2
L&T Opthalmic Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India. ravikanthdanda@gmail.com.
3
Centre for Nanotechnology and Advanced Biomaterials, Shanmugha Arts, Science, Technology and Research Academy University, Tanjore, Tamil Nadu 613 401, India. ravikanthdanda@gmail.com.
4
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India. anil@ibioinformatics.org.
5
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India. vinuth@ibioinformatics.org.
6
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India. gajanan@ibioinformatics.org.
7
Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576 104, India. gajanan@ibioinformatics.org.
8
Centre for Nanotechnology and Advanced Biomaterials, Shanmugha Arts, Science, Technology and Research Academy University, Tanjore, Tamil Nadu 613 401, India. umakrishnan@sastra.edu.
9
Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India. drvk@snmail.org.
10
Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India. drpr@snmail.org.
11
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India. keshav@ibioinformatics.org.
12
Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka 575 108, India. keshav@ibioinformatics.org.
13
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India. pandey@jhmi.edu.
14
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. pandey@jhmi.edu.
15
Departments of Biological Chemistry, Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. pandey@jhmi.edu.
16
L&T Opthalmic Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India. drkk@snmail.org.
17
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India. harsha@ibioinformatics.org.
18
Department of Nanotechnology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India. sailaja.elchuri@gmail.com.

Abstract

Retinoblastoma is a malignant tumour of the retina which most often occurs in children. Earlier studies on retinoblastoma have concentrated on the identification of key players in the disease and have not provided information on activated/inhibited signalling pathways. The dysregulation of protein phosphorylation in cancer provides clues about the affected signalling cascades in cancer. Phosphoproteomics is an ideal tool for the study of phosphorylation changes in proteins. Hence, global phosphoproteomics of retinoblastoma (RB) was carried out to identify signalling events associated with this cancer. Over 350 proteins showed differential phosphorylation in RB compared to control retina. Our study identified stress response proteins to be hyperphosphorylated in RB which included H2A histone family member X (H2AFX) and sirtuin 1. In particular, Ser140 of H2AFX also known as gamma-H2AX was found to be hyperphosphorylated in retinoblastoma, which indicated the activation of DNA damage response pathways. We also observed the activation of anti-apoptosis in retinoblastoma compared to control. These observations showed the activation of survival pathways in retinoblastoma. The identification of hyperphosphorylated protein kinases including Bromodomain containing 4 (BRD4), Lysine deficient protein kinase 1 (WNK1), and Cyclin-dependent kinase 1 (CDK1) in RB opens new avenues for the treatment of RB. These kinases can be considered as probable therapeutic targets for RB, as small-molecule inhibitors for some of these kinases are already in clinical trials for the treatment other cancers.

KEYWORDS:

DEK; DNA damage response; H2AFX; ocular cancer; oncogenic kinases

PMID:
29914080
PMCID:
PMC6100359
DOI:
10.3390/molecules23061454
[Indexed for MEDLINE]
Free PMC Article

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