Zappavigna Vincenzo research activity
1) Study of the mechanisms underlying the perturbation of cell cycle control by NUP98-HOX and other NUP98 fusion oncoproteins.
NUP98 represents one of the most "promiscuous" partner genes in chromosomal translocations causing acute myeloid leukemias (AML), as it forms fusion oncoproteins with more than 20 different proteins, among which nine HOX family members. We published that NUP98-HOXD13 and two other NUP98 oncoproteins, if exogenously expressed, cause substantial perturbations of the chromosome segregation process, inducing aberrant mitoses and aneuploidy, which correlate with an aberrant, untimely degradation of securin, and slippage from an unsatisfied spindle assembly checkpoint (SAC). We are currently studying the mechanism(s) underlying the perturbation of APC/CCdc20 function by NUP98-HOX and other NUP98 fusion oncoproteins. We are also analysing the biological effects of the expression NUP98 fusion oncoproteins and of NUP98 mutant derivatives in human CD34+ hematopoietic stem/progenitor cells.
2) Study of the transcriptional regulation of miR196b and of the CDX2-miR196b-GATA6 regulatory network in colon carcinoma.
Embedded within the HOX gene clusters are found miRNA genes belonging to three different families. The miR-196 family has been predicted not only to target transcripts of 3'-located HOX genes but has been also found to be misexpressed in several tumor tissue samples, strongly suggesting its potential oncogenic role. The mechanism(s) of action of miR-196 in different cancer types is still unknown, so are the transcription factors controlling miR-196 expression. Our data show a direct regulation of miR-196b by the CDX2 transcription factor, which has been reported to be misexpressed in colon cancer. A putative miR-196b target, relevant to colorectal cancer is GATA6, as its expression was described to be altered from the earliest stages of dysplasia continuing to late metastatic lesions. We are currently studying the misregulation of miR196b and of the CDX2-miR196b-GATA6 regulatory network in colon carcinoma.