Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice

Abstract

Fetal cardiomyocytes actively proliferate to form the primitive heart in utero in mammals, but they stop dividing shortly after birth. The identification of essential molecules maintaining this active cardiomyocyte proliferation is indispensable for potential adult heart regeneration. A recent study has shown that this proliferation depends on a low fetal oxygen condition before the onset of breathing at birth. We have established an isolation protocol for mouse fetal cardiomyocytes, performed under strict low oxygen conditions to mimic the intrauterine environment, that gives the highest proliferative activities thus far reported. Oxygen exposure during isolation/culture markedly inhibited cell division and repressed cell cycle-promoting genes, and subsequent genome-wide analysis identified Fam64a as a novel regulatory molecule. Fam64a was abundantly expressed in hypoxic fetal cardiomyocyte nuclei, but this expression was drastically repressed by oxygen exposure, and in postnatal cardiomyocytes following the onset of breathing and the resulting elevation of oxygen tension. Fam64a knockdown inhibited and its overexpression enhanced cardiomyocyte proliferation. Expression of a non-degradable Fam64a mutant suggested that optimum Fam64a expression and subsequent degradation by anaphase-promoting complex/cyclosome (APC/C) during the metaphase-to-anaphase transition are required for fetal cardiomyocyte division. We propose that Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice.

FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and miR-99a-3p)

“…The fusion protein CALM/AF10, t(10;11)(p13;q14), plays a crucial role in acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma [ 41 , 42 ]. Previous studies demonstrated that FAM64A contributes to cell cycle progression [ 43 , 44 , 45 ]. Overexpression of FAM64A was reported in leukemia, lymphoma and several types of solid cancer [ 46 ].…”

FAM64A Promotes Osteosarcoma Cell Growth and Metastasis and Is Mediated by miR-493

“…Recent studies have shown that FAM64A, also named as CATS and PIMREG, participates in malignant transformation [10][11][12][13]. FAM64A was first studied in hematologic carcinomas, which was known as CALM/AF10 interacting proteins.…”

FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis

“…levels strongly correlate with cell proliferation in both malignant and normal cells (18). FAM64A is a multifunctional protein that is involved in regulation of cell cycle progression, subcellular localization of the leukemogenic fusion protein CALM/AF10, and tumorigenesis (18)(19)(20)(21)(22). In a screen for proteins that regulate STAT3 activity, we identified FAM64A as a positive regulator of STAT3, which modulates binding of STAT3 to the promoters of its target genes.…”