Table 1 Regulators of Keap1-Nrf2 pathway and their biological effects in pancreatic cancer

Cullin3

Keap1

Forms the Keap1-Cul3-RBX1 E3 ligase complex and induces Nrf2 polyubiquitination and proteasomal degradation

[36]

UHRF1

Keap1

Down-regulates Keap1 expression by enhancing KEAP1 promoter methylation

[39]

MBD1

Keap1

Down-regulates Keap1 expression by enhancing KEAP1 promoter methylation

[40]

p62

Keap1

Directly binds to Keap1, competitively inhibits the binding of Nrf2 to Keap1, and protects Nrf2 from protein degradation

[30]

aPKCι

Keap1

Directly binds to Keap1, competitively inhibits the binding of Nrf2 to Keap1, and protects Nrf2 from protein degradation

[41]

PALB2

Keap1

Directly binds to Keap1, competitively inhibits the binding of Nrf2 to Keap1, and protects Nrf2 from protein degradation

[42]

KRAL

Keap1

Directly interacts with miR-141 and increases the expression of Keap1

[43]

β-TrCP

Nrf2

Directly binds to Nrf2 and promotes its ubiquitination and proteasomal degradation

[23]

HRD1

Nrf2

Directly interacts with Nrf2 and promotes its ubiquitination and proteasomal degradation

[38]

GSK-3β

Nrf2

Phosphorylates Nrf2 at Ser342 and Ser347 in Neh6 domain

[23]

ALDOA

Nrf2

Increases the expression of Nrf2

[44]

Kras/ERKaxis

Nrf2

Increases the expression of Nrf2

[45,46,47]

GRP78/UPR

Nrf2

Increases the activity of Nrf2

[48]

STAT3

Nrf2

Increases the expression of Nrf2

[14]

APE1/Ref-1

Nrf2

Directly interacts with Nrf2 and inhibits its activity

[49]

dCK

Nrf2

Negatively regulates the NRF2 transcriptional activity

[50]

NRAL

Nrf2

Directly binds to miR-340-5p, inhibits miR-340-5p-mediated repressing activity of the Nrf2–3’UTR, and increases Nrf2 expression

[51]