HMGA2 and the p19Arf-TP53-CDKN1A axis: a delicate balance in the growth of uterine leiomyomas.
Pathogenetically, uterine leiomyomas (ULs) can be interpreted as the result of a monoclonal abnormal proliferation of myometrial cells. Oncogene-induced senescence (OIS) is a frequent phenomenon in premalignant lesions that leads to a growth arrest mainly by the activation of two potent growth-inhibitory pathways as represented by p16(Ink4a) and p19(Arf). The relevance of OIS for the development of UL has not been addressed, but HMGA2, encoded by a major target gene of recurrent chromosomal abnormalities in UL, has been implicated in the repression of the Ink4a/Arf (CDKN2A) locus. This prompted us to examine if HMGA2 contributes to the growth of leiomyomas by repressing this locus. Contrary to the expectations, we were able to show that generally ULs express significantly higher levels of p19(Arf) mRNA than myometrium and that UL with 12q14 approximately 15 rearrangements showed higher expression levels than UL with other cytogenetic aberrations. Furthermore, the finding of a significant correlation between the expressions of p19(Arf) and CDKN1A shows that p19(Arf) triggers senescence rather than apoptosis in UL. Furthermore, the expression levels of HMGA2, p19(Arf), and CDKN1A were found to be correlated with the size of the tumors, indicating that an enhanced growth potential is counterbalanced by the p19(Arf) pathway. Mechanistically, the UL may thus execute a program already present in their cell of origin, where it is activated to protect the genome, for example, in the case of enhanced proliferation. In summary, the results identify the p19(Arf)-TP53-CDKN1A pathway as a major player in the growth control and genomic stability of uterine fibroids.
Markowski
Dominique Nadine
DN
Center of Human Genetics, University of Bremen, Leobener Strasse ZHG, 28359 Bremen, Germany.
von Ahsen
Inga
I
Nezhad
Maliheh Hashemi
MH
Wosniok
Werner
W
Helmke
Burkhard Maria
BM
Bullerdiek
Jörn
J
D017209:Apoptosis; D016922:Cellular Senescence; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D009215:Myometrium / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025743:HMGA2 Protein; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53