Electronic Theses and Dissertations Archive

Date

2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biology

Committee Chair

Amy Abell

Committee Member

Bernie Daigle

Committee Member

Carlos Estrano

Committee Member

Charles Lessman

Committee Member

Omar Skalli

Abstract

During development, stem cells rapidly proliferate and differentiate to form the embryo and the placenta, requiring intensive increases in cellular protein synthesis and changes to the cell architecture. Chaperone proteins, including the small heat shock proteins (HSPs), are critical assistants to protein folding, preventing protein aggregation, and promoting autophagy. Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) is a stress-activated kinase that promotes fetal and placental growth. MAP3K4 activates p38 and JNK in trophoblast stem (TS) cells by phosphorylating MAP2K3 and MAP2K4/7, respectively. In addition, MAP3K4 promotes activation of the PI3K/Akt signaling pathway in part through controlling expression of PDK1 in placental trophoblasts. We also discovered a previously undescribed mechanism controlling the Akt signaling pathway in TS cells, where MAP3K4, CBP, and HDAC6 coregulate expression and activation of IGF1R protein by controlling Igf1r transcript levels. We also discovered TS cells differentiate to placental trophoblasts comprising the junctional zone (JZ) and labyrinth (LAB) placental layers. In this study, we demonstrate that JZ differentiation transiently increases JNK activity, whereas LAB differentiation induces sustained p38, JNK, and Akt activation. Each of these pathways is inhibited in MAP3K4 kinase-inactive (KI) LABKI trophoblasts. JZ and LAB differentiation also induces HSP22 and HSP27 expression and HSP27 phosphorylation; these are also reduced in TSKI and LABKI cells. JZ and LAB differentiation induces GABARAP-positive autophagosomes that are deficient in KI cells. Altogether, our findings demonstrate that MAP3K4 is critical for responses during differentiation in placental trophoblasts.

Comments

Data is provided by the student.

Library Comment

Dissertation or thesis originally submitted to ProQuest/Clarivate.

Notes

Open Access

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