Antiapoptotic action of 1,25-dihydroxyvitamin D3 is associated with increased mitochondrial MCL-1 and RAF-1 proteins and reduced release of cytochrome c

Xuening Wang, George P. Studzinski

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Release of mitochondrial cytochrome c has been recently linked to the activation of the 'executioner' phase of the cellular programs for death by apoptosis. This release is known to be negatively regulated by Bcl-2 and Bcl- XL proteins. We show here that treatment of human leukemia cells HL60 with 1,25-dihydroxyvitamin D3 (1,25D3) results in progressive increases in the levels of cellular antiapoptotic protein Mc1-1, a transient increase in A1 protein level, but no increases in Bcl-2 or Bcl-X(L) proteins. The increase in Mcl-1 protein levels correlates with a reduced extent of apoptotic cell death induced by etoposide or the calcium ionophore A23187. The Mcl-1 protein is primarily localized in the mitochondria, and etoposide- or A23187-induced cytochrome c release is reduced in cells in which the mitochondria contain the Mcl-1 protein demonstrable by immunoblots. Raf-1 protein can also be detected in the mitochondrial fractions that contain Mcl-1 protein but not in the Mcl-1-negative fractions. These findings suggest that in these promyelocytic leukemia cells Mcl-1 has a function analogous to that of Bcl-2 in other cells, i.e., to target Raf-1 to mitochondria and to reduce cell damage-induced release of mitochondrial cytochrome c. Our findings provide a potential mechanism for the antiapoptotic action of 1,25D3 and show that differentiation and apoptosis signaling pathways not only internet but involve a proliferationassociated gene, Raf-1.

Original languageEnglish (US)
Pages (from-to)210-217
Number of pages8
JournalExperimental cell research
Volume235
Issue number1
DOIs
StatePublished - Aug 25 1997

All Science Journal Classification (ASJC) codes

  • Cell Biology

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