Abstract
Nm23/NDP kinases are multifunctional enzymes involved in the general homeostasis of triphosphate nucleosides. Numerous studies have shown that NDPKs also serve as regulatory factors of various cell activities, not always connected to nucleotide phosphorylation. In particular, the nme-1 gene, encoding the NM23-1/NDPKA protein, has been reported as a metastasis suppressor gene. This activity was validated in hepatocellular tumors induced in nm23-1 deficient mice. Yet, data describing the primary physiological functions of nm23-1/NDPKA is still scarce. We have characterized in depth the phenotype of nm23-1 deletion in the mammary gland in mice carrying whole body nm23-M1 invalidation. We also asked why the nm23-M1−/− mutant females displayed severe nursing disability. We found that the growth retardation of mutant virgin glands was due to reduced proliferation and apoptosis of the epithelial cells within the terminal end buds. The balance of pro/anti-apoptotic factors was impaired in comparison with wild type glands. In the lactating glands, the reduced proliferation rate persisted, but the apoptotic factors were unchanged. However, those defects did not seem to affect the gland maturation since the glands lacking nm23-1/NDPKA appeared morphologically normal. Thorough examination of all the functional aspects of the mammary glands revealed that lack of nm23-1/NDPKA does not impact the production or the ejection of milk in the lumen of lobuloalveolae. Interestingly, an epithelial plug was found to obstruct the extremity of the unique lactiferous duct delivering the milk out of the nipple. These cells, normally disappearing after lactation takes place, persisted in the mutant nipples. This work provides a rare instance of nm23-1/NDPKA physiological functions in the mammary glands and reveals its implication as a modulator factor of proliferation and apoptosis in this tissue.
Highlights
Nucleoside diphosphate kinases (NDPKs) are ubiquitous enzymes synthesizing nucleoside triphosphates
They are encoded by 9 genes in humans, forming the family of the non metastatic #23 genes or nme genes. They can be split into two groups according to their levels of homology with the historical isoforms nm23-1/NDPKA and 2/NDPKB [1]. They have first been considered as housekeeping enzymes until the gene nm23-1/nme1 was found involved into the mammary gland metastatic process [2]
Nm23-M1 is expressed in the luminal cells of the mammary gland epithelium
Summary
Nucleoside diphosphate kinases (NDPKs) are ubiquitous enzymes synthesizing nucleoside triphosphates They are encoded by 9 genes in humans, forming the family of the non metastatic #23 (nm23) genes or nme genes. They can be split into two groups according to their levels of homology with the historical isoforms nm23-1/NDPKA and 2/NDPKB [1]. Several explanations have been raised to explain nm implication as a tumor suppressor Among them, it seems that nm genes products interact with cytoskeleton elements leading to modulation of cell/cell and cell/extracellular matrix bonds and they indirectly regulate small G protein activity such as
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