This gene generates several transcript variants which
differ in their first exons. At least three alternatively spliced
variants encoding distinct proteins have been reported, two of
which encode structurally related isoforms known to function as
inhibitors of CDK4 kinase. The remaining transcript includes an
alternate first exon located 20 Kb upstream of the remainder of the
gene; this transcript contains an alternate open reading frame
(ARF) that specifies a protein which is structurally unrelated to
the products of the other variants. This ARF product functions as a
stabilizer of the tumor suppressor protein p53 as it can interact
with, and sequester, MDM1, a protein responsible for the
degradation of p53. In spite of the structural and functional
differences, the CDK inhibitor isoforms and the ARF product encoded
by this gene, through the regulatory roles of CDK4 and p53 in cell
cycle G1 progression, share a common functionality in cell cycle G1
control. This gene is frequently mutated or deleted in a wide
variety of tumors, and is known to be an important tumor suppressor
gene.
