Myeloid leukemia factor-1 is a novel modulator of neonatal rat cardiomyocyte proliferation

Biochim Biophys Acta Mol Cell Res. 2017 Apr;1864(4):634-644. doi: 10.1016/j.bbamcr.2017.01.004. Epub 2017 Jan 10.

Abstract

The present study focuses on the identification of the gene expression profile of neonatal rat cardiomyocytes (NRVCMs) after dynamic mechanical stretch through microarrays of RNA isolated from cells stretched for 2, 6 or 24h. In this analysis, myeloid leukemia factor-1 (MLF1) was found to be significantly downregulated during the course of stretch. We found that MLF1 is highly expressed in the heart, however, its cardiac function is unknown yet. In line with microarray data, MLF1 was profoundly downregulated in in vivo mouse models of cardiomyopathy, and also significantly reduced in the hearts of human patients with dilated cardiomyopathy. Our data indicates that the overexpression of MLF1 in NRVCMs inhibited cell proliferation while augmenting apoptosis. Conversely, knockdown of MLF1 protected NRVCMs from apoptosis and promoted cell proliferation. Moreover, we found that knockdown of MLF1 protected NRVCMs from hypoxia-induced cell death. The observed accelerated apoptosis is attributed to the activation of caspase-3/-7/PARP-dependent apoptotic signaling and upregulation of p53. Most interestingly, MLF1 knockdown significantly upregulated the expression of D cyclins suggesting its possible role in cyclin-dependent cell proliferation. Taken together, we, for the first time, identified an important role for MLF1 in NRVCM proliferation.

Keywords: Apoptosis; Biomechanical stress; Caspase-3; D cyclins; Myeloid leukemia factor-1; Proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis
  • Biomechanical Phenomena
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Proliferation / genetics*
  • Cyclin D / genetics
  • Cyclin D / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Mice
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Nuclear Proteins
  • Oligonucleotide Array Sequence Analysis
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Primary Cell Culture
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proteins / antagonists & inhibitors
  • Proteins / genetics*
  • Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Wistar
  • Stress, Mechanical
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cyclin D
  • MLF1 protein, human
  • Mlf1 protein, rat
  • Nuclear Proteins
  • Protein Isoforms
  • Proteins
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Poly(ADP-ribose) Polymerases
  • Casp3 protein, rat
  • Caspase 3