The Role of IREa and p53 in UVB Sensitivity of Human Keratinocytes

Open Access
- Author:
- Ibinson, Jack
- Area of Honors:
- Immunology and Infectious Disease
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Adam Bleier Glick, Thesis Supervisor
Pamela Hankey Giblin, Thesis Honors Advisor - Keywords:
- IRE1
ER stress
p53
skin cancer
cancer
UV
Unfolded Protein Response
UPR
DNA Damage Response
DDR
UVB
UV-induced DDR
keratinocytes
HaCaT
N-TERT - Abstract:
- The endoplasmic reticulum (ER) is a large membrane-bound organelle in eukaryotic cells that governs protein folding, lipid synthesis, and calcium signaling throughout its extensive network of tubules. Upon an influx of misfolded proteins and external stress, cells enter a state known as ER stress as the ER becomes overwhelmed. To remedy ER stress and restore proper protein homeostasis, cells initiate the Unfolded Protein Response (UPR) with the use of three critical proteins: Activating Transcription Factor 6 (ATF6), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and — the subject of this thesis — Inositol-requiring enzyme 1 (IRE1α). This thesis project aims to investigate the role of IRE1α in the context of the mutant-p53 skin cancer cell response to acute UVB exposure. p53 is a crucial tumor suppressor protein that facilitates cell cycle arrest and recruitment of DNA Damage Response (DDR) proteins to sites of DNA damage in order to prevent mutations after damaging agents. In cases of p53 mutation, the DDR becomes altered, affecting the normal response to DNA damage and providing an opportunity for cancer to develop. Considering that UVB exposure is the most common environmental risk factor for skin cancer development, the response of cells with mutant-p53 to acute UVB exposure may give new insight into the processes of skin cancer development. Research from Glick Lab at Penn State supports a unique role of IRE1α in both the UPR and UV-induced DDR, linking IRE1α to UV-mediated responses and potential skin cancer development. Here, we used immortalized human keratinocytes as an in vitro model for assessing how IRE1α and p53 expression coordinate the cellular response to acute UVB exposure.