Klf4 (rat, Q923V7) - manual literature research

No deep-research provider was available for this review, so this file records a manual
literature survey based on cached publications (publications/PMID_*.md) and PubMed
searches. Every statement carries its source.

Identity and domain architecture

• Q923V7 is an unreviewed TrEMBL entry (482 aa) for rat Klf4 (RGD:621445, GeneID 114505).
  It carries three C-terminal C2H2 zinc fingers (PROSITE PS50157 at 399-428, 429-458,
  459-482), Pfam PF00096 x3, and PANTHER PTHR23235:SF117 "KRUEPPEL-LIKE FACTOR 4"
  [file:rat/Klf4/Klf4-uniprot.txt].
• KLFs bind GC-rich/CACCC elements through the three C-terminal zinc fingers
  PMID:18406357.

DNA binding and transcriptional activation (rat experiments)

• Rat KLF4 (GKLF) was cloned from a rat mesangial cell library in a yeast one-hybrid
  screen with the LAMC1 bcn-1 element; it binds bcn-1 and activates the LAMC1 promoter in
  synergy with Sp1 [PMID:12034813 "We show that GKLF binds bcn-1, but this binding is not
  required for the GKLF-mediated activation of the LAMC1 promoter"; "the synergistic
  action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF
  activation and DNA-binding domain"].
• KLF4 assembles with CREB and p53 at the bradykinin B2 receptor enhancer on chromatin in
  developing rat kidney, with CBP recruitment PMID:15632413.
• In rat aortic VSMCs, GKLF activates the p53 promoter and inhibits proliferation in a
  p53-dependent manner [PMID:17659301 "GKLF overexpression led to an enhanced p53 promoter
  activity and increased p53 mRNA and protein expression"; "p53 induction is essential
  for the interference of GKLF with VSMC proliferation"].
• KLF4 binds two KLF sites in the SM22alpha promoter; binding is modulated by
  acetylation (p300) and deacetylation (HDAC2) [PMID:21252119 "KLF4 was directly bound to
  the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22α
  promoter"; "increasing its interaction with p300"; "increasing its interaction with
  histone deacetylase 2 (HDAC2)"].
• HDAC2 interacts with and deacetylates KLF4; ATRA dissociates the complex
  PMID:19486889.

Transcriptional repression and antiproliferative role in VSMCs

• KLF4 binds the RARalpha 5' regulatory region and down-regulates RARalpha; it also
  inhibits PDGFRbeta expression, blocking PI3K and ERK signalling [PMID:19531492 "Klf4
  directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha
  expression"; "Klf4 inhibits RAR alpha and PDGFR beta expression while blocking PI3K and
  ERK signaling induced by Am80 and PDGF-BB, respectively"]. The effect on PI3K is
  therefore transcriptional and indirect.
• In mouse, KLF4 represses SMC differentiation marker genes via TCE elements, binding them
  in chromatin PMID:12970361; conditional knockout increases neointima after injury, and KLF4 induces
  p21 with p53 PMID:18483411.
• KLF4 mediates p53 transactivation of p21WAF1/Cip1 via a Sp1-like element
  PMID:10749849.

Regulation of Klf4 expression (rat)

• Endothelin-1 and H2O2 induce Klf4 mRNA in neonatal rat cardiac myocytes as an
  immediate-early gene, partly ERK1/2-dependent [PMID:18406357 "H2O2 increased expression
  of Klf2, Klf4 and Klf6"; "Klf2, Klf4 and Klf6 are regulated as IEGs in response to
  ET-1"].
• ATRA and PDGF-BB induce KLF4 in VSMCs PMID:21252119.

Roles known from other mammals (basis of ISO/IEA rows)

• Skin barrier: Klf4-/- mice die at birth from barrier loss PMID:10431239.
• Reprogramming: one of the four Yamanaka factors PMID:16904174.
• Endothelium: anti-inflammatory, induces eNOS and thrombomodulin, reduces leukocyte
  adhesion PMID:17339326.