14-3-3σ regulates keratinocyte proliferation and differentiation by modulating Yap1 cellular localization

Area of Science:

• Dermatology
• Molecular Biology
• Cancer Research

Background:

• The homozygous repeated epilation (Er/Er) mouse mutant exhibits epidermal abnormalities, including hyperproliferative keratinocytes and undifferentiated epidermis.
• Heterozygous Er/+ mice are prone to spontaneous skin tumors and are sensitive to chemical carcinogens.

Purpose of the Study:

• To elucidate the molecular mechanisms of 14-3-3σ in regulating epidermal proliferation, differentiation, and tumor formation.
• To investigate the role of Yap1 as a downstream effector of 14-3-3σ in epidermal homeostasis.

Main Methods:

• Analysis of Er/Er keratinocytes in vivo and in vitro.
• Yap1 nuclear localization assessment in normal and mutant epidermis and tumors.
• Short hairpin RNA (shRNA) knockdown of Yap1 in Er/Er keratinocytes.
• Co-immunoprecipitation assays to study protein interactions.

Main Results:

• Er/Er keratinocytes show failed cytoplasmic sequestration of Yap1, resulting in its nuclear localization.
• Nuclear Yap1 localization is also observed in chemically induced tumors from Er/+ mice.
• Yap1 knockdown in Er/Er keratinocytes reduces proliferation, indicating Yap1's role in epidermal growth.
• Mutant Er 14-3-3σ fails to interact with Yap1.

Conclusions:

• The Er/Er mutation disrupts the 14-3-3σ-Yap1 interaction, impairing Yap1's inhibitory function on nuclear transcription.
• This disruption leads to uncontrolled progenitor cell expansion and impaired differentiation in the Er/Er epidermis.
• 14-3-3σ is critical for maintaining epidermal homeostasis by regulating Yap1 localization and activity.