Transcriptional Activation of the Cyclin A Gene by the Architectural Transcription Factor HMGA2

Abstract

The HMGA2 protein belongs to the HMGA family of architectural transcription factors, which play an important role in chromatin organization. HMGA proteins are overexpressed in several experimental and human tumors and have been implicated in the process of neoplastic transformation. Hmga2 knockout results in the pygmy phenotype in mice and in a decreased growth rate of embryonic fibroblasts, thus indicating a role for HMGA2 in cell proliferation. Here we show that HMGA2 associates with the E1A-regulated transcriptional repressor p120 E4F , interfering with p120 E4F binding to the cyclin A promoter. Ectopic expression of HMGA2 results in the activation of the cyclin A promoter and induction of the endogenous cyclin A gene. In addition, chromatin immunoprecipitation experiments show that HMGA2 associates with the cyclin A promoter only when the gene is transcriptionally activated. These data identify the cyclin A gene as a cellular target for HMGA2 and, for the first time, suggest a mechanism for HMGA2-dependent cell cycle regulation.HMGA2 belongs, together with HMGA1a and HMGA1b, to the HMGA family of nuclear proteins, whose expression has functional implications in the pathogenesis of several human tumors (2,20,47,50). A strong association between the expression of these proteins and the transformed phenotype has been observed since they were first described, in transformed rat thyroid cells (24,25), and was later found in several human neoplasias (e.g., colon, prostate, cervical, and thyroid carcinomas) (4, 10, 17, 51). Their expression is very low, if not absent, in adult tissues and is restricted to embryogenesis (11,28,32,55).The first evidence of a direct role played by these factors in tumorigenesis came from transfection of an antisense construct for HMGA2 in normal rat thyroid cells that prevented the neoplastic transformation induced by myeloproliferative sarcoma virus and kirsten murine sarcoma virus (7). More recently, the increased expression of all three HMGA family members was shown to lead to transformation with anchorageindependent cell growth (53, 54), and the overexpression of HMGA1 was also shown to promote tumor progression in human breast epithelial cells (41). Of additional interest, rearrangements of the HMGA2 gene, resulting in the loss of the acidic C-terminal tail, have been frequently detected in benign human tumors of mesenchimal origin (50). Indeed, transgenic mice expressing the truncated HMGA2 protein develop tumors such as lipomas and natural killer lymphomas (1, 3, 6, 18), while mice expressing wild-type HMGA2 develop pituitary adenomas (19).Despite this evidence, the molecular events and the precise role played by HMGA2 in cell proliferation and tumorigenesis still need to be defined.HMGA proteins contain about 100 amino acid residues and have three DNA-binding domains which have been named AT hooks because of their ability to interact with the narrow minor groove of AT-rich DNA sequences (42). These nuclear proteins, by binding to DNA and/or to transcription factors, can organi...

HMGA2 Regulates Transcription of the Imp2 Gene via an Intronic Regulatory Element in Cooperation with Nuclear Factor-κB

“…In contrast to HMGA1, the role of HMGA2 as an architectural transcription factor is less well studied. To our knowledge, to date, besides Imp2, only five other genes have been identified as target genes of HMGA2, being the CDC2, TK1, and cyclin E genes (34); the DNA repair gene ERCC1 (21); and the cyclin A gene, which is a key factor in cell cycle control (35). In the two latter cases, it has been shown that HMGA2 binds to AT-rich regions in the promoter of these target genes.…”

MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth

“…This gene (CCNA) has not yet been described as a target for let-7b. However, HMGA2, which is a known target of let-7b [18], is a major activator of cyclin A expression [19]. Cyclin A downregulation might thus occur indirectly via let-7b/HMGA2 interaction.…”

SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

“…Previous studies by us and other groups have shown that aberrant expression of architectural transcription factor HMGA2 is associated with the regulation of cell proliferation and gene expression (8,19,20,23,24). We therefore sought to screen for novel HMGA2-interacting proteins that mediate the pleiotropic effects by HMGA2.…”