p53 mediates a default programme of mammary gland involution in the absence of STAT3.
Previous studies have demonstrated a proapoptotic role for the transcription factor STAT3 in involuting murine mammary epithelium, resulting in delayed involution and lower levels of apoptosis in the STAT3 null gland relative to wild-type controls. As p53 was implicated in the eventual involution of the STAT3 null gland, we examined the effect of STAT3 loss in the mammary gland in a p53 null background. Combined loss of STAT3 and p53 severely perturbed involution, with hyperdelayed loss of epithelium and reappearance of adipocytes. The early apoptotic response was almost completely abrogated, although elevated levels of delayed apoptosis persisted at days 6, 17 and 4 weeks of involution in STAT3-p53 doubly null mammary glands. A 5.7-fold upregulation of the cyclin-dependent kinase inhibitor p21Waf1 at 3 days of involution in STAT3 null glands was abolished in STAT3-p53 doubly null glands -- suggesting that the critical factor triggering delayed involution in the STAT3 null gland is a p53-dependent rise in p21Waf1 levels around day 3 of involution. Further, STAT3-p53 doubly null glands showed significantly higher levels of proliferation compared to STAT3 or p53 singly null (or wild-type) glands at days 6, 17 and 4 weeks of involution. Combined loss of STAT3 and p53 therefore results in hyperdelayed involution, demonstrating their synergistic physiological roles in normal involution. This inappropriate retention of p53-deficient cells may represent a novel mechanism of tumour predisposition.
Matthews
James R
JR
School of Biosciences, Cardiff University, Cardiff, UK.
Clarke
Alan R
AR
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005838:Genotype; D015151:Immunoblotting; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008321:Mammary Glands, Animal / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine