Lamin A/C Maintains Exocrine Pancreas Homeostasis by Regulating Stability of RB and Activity of E2F

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: Elenbaas JS, Cunha JB, Azuero-Dajud R, Nelson B, Oral EA, Williams JA, Stewart CL, Omary MB
Förläggare: W B SAUNDERS CO-ELSEVIER INC
Publiceringsår: 2018
Tidskrift: Gastroenterology
Tidskriftsakronym: GASTROENTEROLOGY
Volym: 154
Nummer: 6
Artikelns första sida, sidnummer: 1625
Artikelns sista sida, sidnummer: 1629
Antal sidor: 13
ISSN: 0016-5085


Abstrakt

Lamins have important roles in nuclear structure and cell signaling. Several diseases are associated with mutations in the lamin A/C gene (LMNA in humans). Patients with familial partial lipodystrophy caused by LMNA mutations develop pancreatitis, but lamin function in the pancreas and how these mutations affect pancreatic regulation are unknown. We generated mice with inducible exocrine pancreas-specific disruption of Lmna and showed that LMNA is lost from most exocrine pancreas cells. LMNAknockout pancreata develop endoplasmic reticulum stress with loss of acinar cell markers, increased autophagy, apoptosis, and cell proliferation, compared to CreERT2(-) mice (littermate controls). Disruption of Lmna led to a phenotype that resembled chronic pancreatitis, with increased Sirius Red staining and alpha-smooth muscle actin in male LMNA-knockout mice compared to littermate males, but not in female mice. LMNA-knockout pancreata have reduced levels of RB and activation of E2F, based on increased expression of E2F target genes. Therefore, lamins maintain pancreatic homeostasis by regulating RB stability and E2F activity.


Nyckelord

Intermediate filament, mouse model, Nuclear Lamina, Partial Lipodystrophy

Senast uppdaterad 2019-26-06 vid 05:42