The role of Rhox homeobox factors in tumorigenesis 

Abstract

Homeobox genes encode transcription factors that have well-established roles in embryonic development. We recently discovered the Rhox genes, a new family of homeobox genes, which are selectively expressed in the developing embryo, postnatal and adult gonads, and accessory tissues associated with mammalian reproduction. The largest and best-characterized Rhox cluster is found in mouse. However, all mammals examined to date possess a set of Rhox genes that, while they may vary in number by species, appear relevant to reproduction and are located in the syntenic region of the X chromosome. Rhox5, the founding member of the family, was initially cloned from a screen to identify tumorigenic antigens from T-cell lymphomas, and was later found to be widely expressed in tumors from tissues of diverse origins that do not normally express the Rhox genes. This aberrant upregulation appears to be a general feature of many Rhox genes, but the implications of this misexpression remain largely uninvestigated. In this review, we will discuss the latest findings on the normal and abnormal roles of the Rhox genes and their potential contributions to the formation and progression of tumors.

Rhox8 Ablation in the Sertoli Cells Using a Tissue-Specific RNAi Approach Results in Impaired Male Fertility in Mice1

“…However, our knowledge of their postnatal roles governing cellular proliferation, differentiation, and survival in both normal tissues and cancers is still growing [3][4][5]. Rodent genomes contain ;200 homeobox genes, 25% of which are known to be expressed in the testis [3,5].…”

“…However, our knowledge of their postnatal roles governing cellular proliferation, differentiation, and survival in both normal tissues and cancers is still growing [3][4][5]. Rodent genomes contain ;200 homeobox genes, 25% of which are known to be expressed in the testis [3,5]. However, a clear function for the majority has yet to be identified, as their ablation often results in malformation of an essential organ, leading to pre-or perinatal lethality, precluding the examination of their role in fertility [3].…”

Regulated Expression of Rhox8 in the Mouse Ovary: Evidence for the Role of Progesterone and RHOX5 in Granulosa Cells1

“…8A). Rhox5 was highly expressed in SIGC, which is likely due in part to normal granulosa-specific promoter induction but also to the immortalization of this cell line by TRP53 mutation [41] as Rhox5 is well known to be aberrantly expressed in tumor cells regardless of their tissue of origin [14]. SIGC were transiently transfected with the pGL3-Rhox8 promoter constructs containing (1412 nt) and lacking (1357 nt) the PRE sequence.…”

“…Approximately 200 homeobox genes have been characterized in rodents, and ;33% are known to be expressed in the gonads [12,14]. However, a clear function for most of them has yet to be identified as their ablation often results in malformation of a key system, leading to pre-or perinatal lethality that precludes examination of their role in fertility [12].…”

The RHOX Homeodomain Proteins Regulate the Expression of Insulin and Other Metabolic Regulators in the Testis

“…This role is likely to be conserved in other mammals, because the rat and human RHOX genes are also selectively expressed in reproductive tissues (19,(25)(26)(27)(28)(29)(30). Targeted deletion of the founding member of the Rhox cluster, Rhox5, in mice results in male subfertility, marked by increased germ cell apoptosis, reduced sperm number, and a reduced proportion of sperm with normal motility (18,19,28,31). Because RHOX5 is not detectably expressed in germ cells but instead is expressed in the directly adjacent Sertoli nurse cells (32)(33)(34)(35), we have previously hypothesized that the increased germ cell apoptosis in Rhox5-null mice is most likely due to the loss of one or more Sertoli cell-expressed RHOX5-dependent survival factor (31,36).…”