The p16INK4a/CDKN2A tumor suppressor and its relatives

FOXO transcription factor-dependent p15INK4b and p19INK4d expression

“…9p21, which codes p15 INK4b , p16 INK4a and p14 ARF genes, are often observed in many cancers (Ruas and Peters, 1998). p14 ARF is an activator of p53 and indirectly induces p21 CIP1 expression (Stott et al, 1998).…”

ARF antagonizes the ability of Miz-1 to inhibit p53-mediated transactivation

“…This locus (also known as CDKN2A in human) is among the most frequently disrupted sites resulted from chromosomal deletion, mutation, or epigenetic silencing in a large number of human tumors (Ruas and Peters, 1998;Sharpless and DePinho, 1999). Activation of ARF by hyperproliferative oncogenic stimuli, including c-Myc, E1A, E2F1, Ras, or b-catenin, suppresses the growth of the affected cells by promoting cell growth arrest, senescence, or apoptosis (Sherr, 2001;Lowe and Sherr, 2003;Sharpless, 2005).…”

INK4 Family —A promising target for ‘gene-regulating chemoprevention’ and ‘molecular-targeting prevention’ of cancer

“…As described above, inactivation of the p16 INK4a gene is one of the most frequent defects in human malignant tumors (4). On the other hand, genetic alteration of the p18 INK4c gene is a rare event in human tumors (3).…”

“…1). Inactivation of this gene through gene deletions, point mutations or transcriptional silencing by methylation of the promoter is one of the most frequent defects that contribute to human oncogenesis, thereby establishing p16 INK4a as a tumor-suppressor gene product in many human tumors (4). p16 INK4a -deficient mice are susceptible to malignant tumors (5,6), and germ-line mutational analysis indicates that mutations of this gene in humans are associated with familial syndromes such as malignant melanoma and pancreatic cancer (7).…”

“…On the other hand, most human tumors have genetic or epigenetic alterations in their components of the RB pathway (4,37). It is unknown whether any connection between the TPA-PKC pathway and RB pathway exists.…”